MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

ZHORŠENÍ OBEZITY - rizikové

Arachidonic acid

  • PUFA that has substantial evidence supporting its role in pro-inflammatory conditions
  • Widely available for intake
  • In high quantities in many food items including
    • Fish
    • White meat
    • Red meat
    • Eggs
    • Dairy
    • Vegetable oils such as
      • Peanut oil
      • Canola oil
      • Sesame oil [38]
  • In Western diets AA is a major source of PUFA
    • In eggs, dairy, fish, and meats
  • A key player in promoting inflammation
    • Precursor for numerous eicosanoids
      • Fatty acid derived molecules that mediate inflammatory responses
        • Prostaglandins (PGs)
        • Thromboxanes
        • Leukotrienes [38]
  • AA is converted by the enzymes cyclooxygenase- (COX-) 1 and COX-2
    • The inducible form
    • To PGs of which prostaglandin E2 (PGE2)
      • Pro-inflammatory
      • Ability to inhibit the pro-inflammatory cytokines TNF-alpha and IL-1 [38]
  • COX-2 up-regulation occurs
    • During NFkappaB activation
    • In response to IL-1B
    • AA induces [38]
  • AA has been shown to induce 11 genes regulated by NFkappaB in a human prostate cancer cell line PC-3 including
    • COX-2
    • I?Ba
    • NFkappaB
    • Granulocyte macrophage stimulating factor (GM-CSF)
    • IL-1B
    • CXCL-1
    • TNF-alpha
    • IL-6
    • LTA
    • IL-8
    • PPAR gamma
    • Intercellular adhesion molecule 1 (ICAM-1) [38]

Ay/a mice

  • Decreased melanocortin signaling
    • Due to the binding to melanocortin receptors of the agouti protein
      • A competitive antagonist of melanocortin receptor signaling with a high affinity for MC4-R
  • Ay/a mice develop a late-onset obesity
    • Accompanied by a central resistance to leptin anorexigenic function (Halaas et al., 1997)

Avy mutation (Agouti mice)

  • Ectopic expression of agouti protein
    • Paracrine signaling molecule
    • Normally regulates the production of yellow pigment in fur
    • Binds antagonistically to the melanocortin 4 receptor in the hypothalamus
      • Inducing hyperphagic obesity (Wolff et al., 1999)[1]
  • Epigenetic metastability of the Avy locus
    • Genetically identical Avy/a mice vary dramatically in the degree of DNA methylation at Avy
      • Také potom i v coat color and adult adiposity (Wolff et al., 1999) [1]



C18 ceramide

  • Increased in the skeletal muscle of obese individuals
  • Decreases with exercise.

CerS1 enzyme inhibitor

  • Potent effects in reducing fat deposition and weight gain in mice fed a high fat diet
  • This effect is mediated through enhanced oxidative metabolism of fatty acids, thereby reducing fat storage.

Myonectin

  • C1q/TNF-related protein isoform 15 (CTRP15) on locus 2q37.3.
  • Expression is stimulated by:
    • Exercise
    • Nutrients
      • Increase 2 hours after the intake of glucose or lipids [6]
  • Stimulation of myonectin secretion
    • By exercise
    • lipids [6]
    • Glucose
  • Decrease plasma-free fatty acids levels
    • Stimulation of their uptake in adipose tissue and liver
      • By an increase of scavenger and transporter proteins
        • CD36
        • Fatty acid transporter protein- (FATP-) 1
        • Fatty acid binding protein- (FABP-) 4 [6]
  • no effects on adipocyte lipolysis and glucose homeostasis
  • Acts on the liver
    • Inhibit autophagy through the activation of the PI3K/Akt/mTOR pathway [6]
  • Decreased myonectin levels in high-fat diet-fed mice
    • Decreased mRNA levels in skeletal muscle [6]
  • Increased circulating myonectin in obese Zucker rats
    • Genetically defective in the leptin receptor [6]
    • Consistently present hyperleptinemia [6]
  • Leptin acts on the myocyte in order to induce the expression of the myonectin gene
  • Serum myonectin levels were observed to be unchanged in calorie restricted rats [6]
  • Decreased myonectin mRNA but increased intramuscular myonectin levels on Zucker rats after exercise
  • Cultured mice myotubes with palmitate-induced insulin resistance had lower levels of myonectin and FNDC5 expression
    • Decreased Akt activation
    • Palmitate was observed to decrease PI3K and to increase p38 expression [6]

Acetyl-coenzyme A carboxylase (ACC)

  • Converts acetyl-CoA to malonyl-CoA
    • A building block for fatty acid synthesis

Acetyl coenzyme A (AcCoA)

  • Product of pyruvate dehydrogenase in the mitochondria
  • End product of the mitochondrial fatty acid ß-oxidation pathway
  • Central biosynthetic precursor
    • Fatty-acid synthesis
    • protein acetylation
      • Histone acetyltransferases modify histone proteins
        • Modifikace chromatin structure
  • Primarily generated from
    • Glucose-derived pyruvate through
      • The citrate shuttle
      • ATP citrate lyase in the cytosol [1]
  • Converted to malonyl-CoA
    • Essential precursor for fatty acid biosynthesis [5]
  • TCA cycle initiator

Activin

  • Role in the proliferation of white adipocytes [80]

Adenovirus ptačí

Adenoviry lidské

Ad-5

Myši

  • Adenovirus type 5 (Ad-5) induced adiposity in mice (So et al 2005) [1]

Ad-9

  • Enhance 3T3-L1 differentiation
  • Reduce leptin secretion in vitro (Vangipuram et al 2007)[1]

Ad-31

  • Increase 3T3-L1 differentiation in vitro (Whigham et al 2006) [1]

Kuřata

  • Increased adiposity in chickens [1]

Ad-36

  • Increases adiposity in experimentally infected chickens, rats, mice and marmosets (non-human primates) (Dhurandhar et al 2000; 2001; 2002; Pasarica et al 2006)[1]
  • Without inducing detectable hyperphagia
  • Reduces serum cholesterol and triglycerides (Dhurandhar et al; 2000,Dhurandhar et al; 2001; 2002,) [1]

Kosmani - Marmosets

  • Infekcí 4x gain in body weight [1]
  • Increase in total body fat (36±6 g vs 23±3 g) [1]

Potkani

  • Central and peripheral effects (Pasarica et al 2006)
  • Decreased norepinephrine levels in the paraventricular nucleus, arcuate nucleus, dorso-medial hypothalamus and ventro-medial hypothalamus
  • Dopamine and 5-hydroxyindolacetic acid also reduced in some of these brain regions
  • Increased whole body insulin sensitivity
  • Enhanced expression of genes involved in the adipogenic and de-novo lipogenesis pathway:
    • Fatty acid synthase (FAS) [1]
    • Acetyl-CoA carboxylase (ACC-1) (Vangipuram et al 2007) [1]
  • 4 dny po infekci Ad36 spreads to adipose tissue, liver, kidney, and brain
  • Lowers inflammatory cytokine levels
  • Infected rats have increased epididymal fat pad weight (Pasarica et al 2008b) [1]
  • Ad36 could be used as a tissue engineering tool for building adipose tissue [1]

In vitro lidské buňky

  • Differentiation and lipid accumulation of 3T3-L1 and human primary preadipocytes (Vangiparum et al 2004; Rathod et al 2009)[1]
  • Viral mRNA expression required for this adipogenic effect (Rathod et al 2007) [1]
  • Activates phosphotidyl inositol kinase (PI3K)
  • Aktivuje cAMP pathways [1]
  • Increases cell replication [1]
  • Zvyšuje expressi PPAR?, CEBP/ß [1]
  • Induces differentiation and lipid accumulation in 3T3-L1 cells and human adipose derived stem cells (hASC) (Rogers et al 2007; Rathod et al 2009) [1]
  • Robustly induces adipogenic commitment, differentiation and lipid accumulation (Pasarica et al 2008a).[1]
  • E4 orf-1
    • Viral gene
    • Required and sufficient for this adipogenic effect of Ad-36 (Rogers et al, 2007) [1]

In vitro hlodavčí buňky

  • Ad-36 reduces leptin expression and secretion in rodent fat cells
  • Increases glucose uptake by increase of PI3K activation in:
    • Primary rodent adipocytes (Vangipuram 2007)
    • Human adipose tissue explants or hASC (Rogers et al 2007, Vangipuram et al 2007)
    • Human primary skeletal muscle cells (Wang et al 2008) [1]
  • In Ad-36 infected adipocyte progenitors
    • Increased glucose uptake
    • De-novo lipogenesis
    • Greater replication, differentiation
    • Lipid accumulation [1]

Lidé

  • Natural infection associated with human obesity
  • 17% of the 500+ subjects screened, showed seropositivity to Ad-36 (Atkinson et al 2005) [1]
    • 30% percent of the obese
    • 11% of the non-obese subjects
  • Obese and non-obese seropositive groups
    • Significantly heavier than seronegative counterparts
  • Ad-2 or Ad-31 non-adipogenic adenoviruses (Whigham et al 2006) showed equal distribution among the obese and non-obese groups
    • no association with BMI
      • = Ad-36 seropositivity neznamenala increased propensity to catch infection
      • = Ad36 causatively contributed to their obesity
  • Seropositivity associated with lower levels of serum cholesterol and triglycerides (Dhurandhar et al 2000; 2001; 2002)[1]
  • In twins discordant for antibody status
    • Seropostive twins were heavier and fatter compared to their seronegative counterparts (Atkinson et al 2005) [1]

Ad-37

  • Animals developed increased adiposity (Dhurandhar et al 1990; 1992; 2000; 2001; 2002; Whigham et al 2006; So et al 2005) compared to controls despite similar food intake [1]
  • Enhance 3T3-L1 differentiation
  • Reduce leptin secretion in vitro (Vangipuram et al 2007)[1]

Adipocyte differentiation transcription of specific genes

  • 1 early markers
  • 2 after
    • C/EBPs
    • PPAR alpha
  • 3 lipogenic proteins
    • FAS,
    • GPD,
    • ME,
    • Glut4,
    • AP2,
    • ACC,
    • Beta-adrenergic receptors
    • Many others
  • 4 Later markers
    • PEPCK
    • The alfa-2 adrenergic receptors
    • Leptin
    • Adipsin (Ailhaud et al., 1992) [80]

Rozdíly

  • Adipocyte differentiation is different in vivo and in vitro
    • More complex than previously though
    • Some genes were expressed only in cell lines
    • Others only in cells derived from tissues “in vivo” [80]

Adipogeneze

Acetyl coenzyme A (AcCoA)

  • Product of pyruvate dehydrogenase in the mitochondria
  • End product of the mitochondrial fatty acid ß-oxidation pathway
  • Central biosynthetic precursor
    • Fatty-acid synthesis
    • protein acetylation
      • Histone acetyltransferases modify histone proteins
        • Modifikace chromatin structure
  • Primarily generated from
    • Glucose-derived pyruvate through
      • The citrate shuttle
      • ATP citrate lyase in the cytosol [1]
  • Converted to malonyl-CoA
    • Essential precursor for fatty acid biosynthesis [5]
  • TCA cycle initiator

Citrate-malate cycle

  • Oxidation-reduction balance
  • Simultaneous transfer of the acetyl group
    • From its site of formation
    • To its site of utilization [3]

Adenosine triphosphate [ATP]-citrate lyase = ATP-citrate lyase = ACL

  • Citrate exits the mitochondria to be converted by ATP-citrate lyase to acetyl-CoA for lipid synthesis
  • ACL is required for malonyl-CoA formation
  • Mammalian lipogenesis and cholesterogenesis
  • Linking cellular glucose catabolism and lipogenesis
  • Converting cytosolic citrate to acetyl-coenzyme A (CoA) [6]

Aktivace

  • Regulated in vitro allosterically by phosphorylated sugars as well as covalently by phosphorylation

Hepatic ACL deficiency

  • Significantly down-regulated expression of gluconeogenic genes in the liver
  • Enhanced insulin sensitivity in the muscle
  • Improved systemic glucose metabolism [6]

Inhibice ACL

  • Suppressing ACL expression
    • Proposed to prevent tumor growth [7]
    • Via small interfering RNA
    • Decreased global histone acetylation
      • In several different mammalian cell types
      • Histone acetylation depended on glucose
        • Fatty acids unable to substitute
        • Requirement for a cytosolic or nuclear (not mitochondrial) pool of acetyl-CoA [7]
  • L-glutamate
    • In vitro in differentiating adipocytes
      • Prevented the expression
        • Glut4
        • Hexokinase 2 (HK2)
        • Phosphofructokinase-1 (PFK-1)
        • Lactate dehydrogenase–A (LDH-A)
      • Rescued by treating cells with acetate
  • Potentially novel class of hypolipidemic agents
    • Citric acid analogues 5-16
      • Irreversible inhibitors of the enzyme
        • Active-site nucleophile (thiol)
      • Reversible inhibition
        • Compounds 5, 10, and 12-16 [7]
  • ShRNA-ACL - small hairpin RNA (shRNA)
    • Inhibition of ACL expression
    • Decreased glucose incorporation into palmitate
    • Increased fatty acid oxidation in INS 832/13 cells [8]

Fatty acid synthase (FAS)

Acetyl-coenzyme A carboxylase


Hypoxie - isocitrate dehydrogenase-1 (IDH1)-dependent pathway

  • A reductive metabolism of ?-ketoglutarate
    • Carboxylation of glutamine-derived ?-ketoglutarate
  • Synthesize AcCoA for de-novo lipid synthesis
  • Active in most cell lines under normal culture conditions
  • Cells grown under hypoxia almost exclusively
  • Renal cell lines deficient in the von Hippel–Lindau tumour suppressor protein
    • Preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels [5]

Cellular cyclic AMP

  • Zvýšení
    • Potlačení syntézy MK během minut
      • Changes in glucose transport
      • Pokles pyruvate kinase akt.
      • Pokles pyruvate dehydrogenase akt.
        • Changes in phosphorylation of the alpha subunits [4]
      • Pokles acetyl-CoA carboxylase akt.

PPAR-gamma agonists

  • Efficiently promote adipocyte differentiation from pre-adipocytes (Kanayama et al 2005) [1]
  • Activated receptors (PPARs) which play a major role in adipocyte differentiation and energy storage [2]

Inzulín

  • Marked increase in oxygen consumption during lipogenesis stimulated by insulin in adipose tissue [3]
  • Stimulates fatty acid synthesis in white and brown fat cells as well as in liver and mammary tissue [4]
  • Stimulating pyruvate dehydrogenase phosphatase [4]
    • Fosforylace Acetyl-CoA carboxylase within fat cells on a specific site on the enzyme [4]

Adrenalín

  • Small increase in the overall level of phosphorylation
    • Enhanced phosphorylation of different sites
      • Cyclic-AMP-dependent protein kinase ? [4]


Literatura:

[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.
[2] Association of Endocrine Disruptors and Obesity: Perspectives from Epidemiologic Studies. Citováno: 2012-03-30 < www.ncbi.nlm.nih.gov/pmc/articles/PMC3005328/?tool=pmcentrez >.
[3] MELODEE S. KORNACKER AND ERIC G. BALL. CITRATE CLEAVAGE IN ADIPOSE TISSUE, DEPARTMENT OF BIOLOGICAL CHEMISTRY, HARVARD MEDICAL SCHOOL. Communicated July 22, 1965 [Internet]. [citován 2012 dub 8]. < www.ncbi.nlm.nih.gov/pmc/articles/PMC219762/pdf/pnas00161-0245.pdf >.
[4] 1. The role of phosphorylati... [Philos Trans R Soc Lond B Biol Sci. 1983] - PubMed - NCBI [Internet]. [citován 2012 dub 8]. < www.ncbi.nlm.nih.gov/pubmed/6137007 >.
[5] Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia: Nature: Nature Publishing Group [Internet]. [citován 2012 dub 8]. Available z: < www.nature.com/nature/journal/vaop/ncurrent/full/nature10602.html >.
[6] Abrogation of hepatic ATP-citrate lyase protects ... [Hepatology. 2009] - PubMed - NCBI [Internet]. [citován 2012 dub 8]. Available z: < www.ncbi.nlm.nih.gov/pubmed/19177596 >.
[7] BIOCHEMISTRY. A Glucose-to-Gene Link [Internet]. [citován 2012 dub 8]. www.ncbi.nlm.nih.gov/pmc/articles/PMC2788238/?tool=pubmed
[8] Guay C, Madiraju SR, Aumais A, Joly E, Prentki M. A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion. PMID:17928289[PubMed - indexed for MEDLINE] www.ncbi.nlm.nih.gov/pubmed/17928289


PPAR-gamma agonists

  • Efficiently promote adipocyte differentiation from pre-adipocytes (Kanayama et al 2005) [1]
  • Activated receptors (PPARs) which play a major role in adipocyte differentiation and energy storage [2]

Literatura:

[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.
[2] Association of Endocrine Disruptors and Obesity: Perspectives from Epidemiologic Studies. Citováno: 2012-03-30 < www.ncbi.nlm.nih.gov/pmc/articles/PMC3005328/?tool=pmcentrez >.

If - 20 kg = less need of 20 kcal x 24 = 480 kcal = 2000 kj difference in E need



Adrenalín

  • Small increase in the overall level of phosphorylation
    • Enhanced phosphorylation of different sites
      • Cyclic-AMP-dependent protein kinase ? [4]

2-adrenergic receptor

  • Inhibuje lipoylyzu WAT

Agouti-related peptide


Avy mutation (Agouti mice)

  • Ectopic expression of agouti protein
    • Paracrine signaling molecule
    • Normally regulates the production of yellow pigment in fur
    • Binds antagonistically to the melanocortin 4 receptor in the hypothalamus
      • Inducing hyperphagic obesity (Wolff et al., 1999)[1]
  • Epigenetic metastability of the Avy locus
    • Genetically identical Avy/a mice vary dramatically in the degree of DNA methylation at Avy
      • Také potom i v coat color and adult adiposity (Wolff et al., 1999) [1]

Anandamide

  • Kanabinoid

Androgen deficiency

In men

  • Contributes to the development of metabolic syndrome and type 2 diabetes (T2D)
  • Men will spend a significant proportion of their live in a state of testosterone deficiency
    • Increases type 2 diabetes (T2D) risk [51]
  • Leads to hypogonadism
  • Total testosterone levels were always lower in diabetic men than in non-diabetic controls
  • Higher testosterone levels were associated with a lower risk of incident diabetes
  • Diabetic men still have lower testosterone levels even after adjustment for BMI
  • Impaired fasting glucose and glucose intolerance
    • Independently of obesity and metabolic syndrome in men
  • Inverse correlation between total serum testosterone and the amount of visceral adipose tissue
  • True in all situations of androgen deficiency:
    • Hypogonadism in older men
    • Inherited testosterone deficiency
      • Klinefelter's syndrome [51]
    • Androgen deprivation during treatment for prostate carcinoma
  • Associated with low PGC1 alfa expression levels in muscle
  • Promotes insulin resistance in skeletal muscle
  • Decrease in PGC1 alfa-mediated oxidative and insulin sensitive muscle fibers
  • Castration of male rats
    • Followed by a marked insulin resistance in skeletal muscle under euglycemic, hyperinsulinemic clamp conditions
    • Treatment with physiological doses of testosterone
      • Completely abolishes these perturbations in insulin sensitivity [51]
  • Could contribute to the accumulation of excess fat, establishing a vicious cycle [52]
  • Hypogonadism induce
    • Muscle mass reduction
    • Visceral fat mass increase
    • Insulin resistance
    • Increase of the activity of lipoprotein lipase (LPL)
      • Regulator of triglyceride uptake in the fat cell, preferentially in abdominal fat [52]
  • Induces expansion of fat mass
  • Subsequent dysregulation
    • Insulin sensitivity
    • Blood pressure
    • Vascular reactivity
    • Immunity
    • Insulin resistance
      • Reduced production of SHBG
        • Reduction in testosterone
          • Expansion of adipose mass
            • Increase in aromatase (ARO) activity
              • Peripheral conversion of testosterone to estradiol
                • Increased estrogen levels induce a reduction of LH pulse
                  • Reduction in androgen production [69]
  • Excess of circulating leptin
    • Disrupts testicular steroidogenesis
      • Suppression of androgen production


Falling testosterone levels in men

  • Contributor to poor life quality
  • V.s. effects of ageing on the hypothalamic-pituitary-gonadal (HPG) axis
  • Increasing prevalence of obesity and chronic illness
  • Only small minority of ageing men do testosterone levels fall below the normal range
  • Studies failing to show consistent benefit suplementace
  • Clinical syndrome
  • Sub-physiological testosterone concentrations
  • Disruption of the HPG axis [52]

Klinefelter's syndrome (KS)

  • Manifests before or during puberty
  • Chromosomal aberration (mostly 47,XXY) affecting ~0.2% of male newborns [52]
  • Markedly low testosterone levels
  • Elevated gonadotrophin levels (primary hypogonadism)
  • Small testes
  • Decreased libido, erectile dysfunction
  • Poor beard growth
  • Infertility (with azoospermia) [52]
  • Tall stature
  • Sparse pubic hair
  • Gynaecomastia
  • Decreased muscle mass [52]
  • Decreased muscle strength
  • Low bone mineral density (BMD)
  • Anaemia
  • Decreased physical function [52]
  • Increased risk of
    • Diabetes
    • Obesity [52]
    • Bone fracture
  • Increased mortality [52]

Hypogonadism after puberty - hypothalamic-pituitary disease

  • E.g. tumour, infiltration, trauma, radiation [52]
  • Low testosterone levels
  • Low gonadotrophin levels (secondary hypogonadism)
  • Tend to develop the same features as men with KS with the exceptions of: [52]
    • Small testis [52]
    • Poor beard growth
    • Abnormal height
  • Can occur also due to disruption at more than one level of the HPG axis [52]
    • Opioids in the hypothalamus, pituitary and testis inhibit secretion of:
      • Gonadotropin-releasing hormone (GnRH) [52]
      • Luteinizing hormone [52]
      • testosterone [52]

Testosterone levels fall with ageing

  • European Male Ageing Study (EMAS)
    • 2,736 men aged >40 for
    • Average of 4.4 years
    • 0.1 nmol/l (0.04%) per year reduction in total testosterone
    • 3.83 pmol/l (0.77%) per year reduction in free (not protein bound) testosterone concentrations
    • Fall below the normal range in a minority of ageing men [52]
  • Boston Area Community Health Survey (BACH)
    • 16 and 26% of men aged 70–79 have a total testosterone concentration that is <10.5 nmol/l
    • 11 and 22% of men aged <50 [52]
  • Not all studies have observed lower testosterone levels in older men
    • Healthy men describe no difference in testosterone concentrations between older and younger [52]
  • Multiple mechanisms
    • Testicular and hypothalamic function decline with age
      • Leydig cell number is ~44% lower in men aged 50–76 than in men aged 20–48
      • Secretory capacity of the testes is substantially lower in older men
      • Declining testicular function appears to be the main cause [52]
    • Hypothalamic GnRH secretion is lower in older men
      • But not pituitary LH reserve [52]
    • Obesity contributes to the decline in testosterone
      • Total and visceral fat mass increase with ageing peaking normally at 65 years
      • Obese men (BMI > 30 kg/m2) x (BMI 20–25 kg/m2)
        • Lower total
        • Lower free testosterone
        • Decline more quickly
        • LH concentrations are not elevated
          • Suggesting a hypothalamic-pituitary defect
            • Elevated cytokine concentrations
            • Insulin resistance [52]
    • Chronic illness
      • Role in the fall in testosterone levels
      • Lower testosterone levels than healthy men
      • LH concentrations are not elevated
      • Cardiovascular disease (CVD) and type 2 diabetes (T2DM)
        • Increased concentrations of pro-inflammatory cytokines [52]
    • Statin use [52]
    • vitamin D deficiency [52]
    • Adult onset male hypogonadism [52]
      • Non-specific [52]
      • Overlap with many symptoms that develop with normal ageing
        • Loss of libido increased
        • Erectile dysfunction increased
          • Total testosterone <11 nmol/l
          • Free testosterone <220 pmol/l
            • ~3% of men aged 60–69 [52]
            • ~0.1% of men aged 40–49 [52]
      • Symptoms of hypogonadism do not correspond to low testosterone concentrations [52]



Men on androgen depletion therapy for prostate cancer

  • At high risk to develop T2D
  • Marked hyperglycemia and decreased pancreatic ß-cell function [51]
  • Men undergoing androgen deprivation therapy for nonmetastatic prostate cancer
    • Significant increase of BMI and fat mass
    • Increased incidence of diabetes and cardiovascular disease [52]

Inhibitory aromatázy u mužů

  • Aromatization of testosterone into 17ß-estradiol (E2)
    • Critical to energy homeostasis in males
      • testosterone functions as a prohormone in men
        • To provide E2 for tissue metabolism [51]
  • Orchidectomized male rodents
    • Treated with either testosterone or E2
      • Remain lean [51]
    • Treated with the pure androgen DHT –that cannot be converted to E2
      • Develop obesity [51]
  • Restoration of adiposity was due to testosterone conversion into E2 acting on ERs
    • This is also true in men for whom testosterone replacement suppresses adiposity
      • Blocked in the presence of an aromatase inhibitor [51]


Mutations that increase visceral obesity in males

  • Aromatase
  • ER genes
  • CAG repeat polymorphisms in the AR gene
    • Decreases AR-mediated gene transcription
      • Genetic androgen resistance [51]
  • Male mice with global deletion of the AR
    • Develop late onset visceral obesity
    • With leptin resistance
    • Insulin resistance
    • Increased lipogenesis in adipose tissue and liver [51]


Dopamine agonist therapy

  • First-line therapy for men with hyperprolactinaemia
  • Increase testosterone levels

Low testosterone level and desire of fertility

  • Gonadotrophin therapy
  • Pulsatile gonadotrophin-releasing hormone
    • If LH levels are not elevated



Testosterone replacement therapy in men

  • Associated with a significant reduction in
    • Fasting plasma glucose
    • HBA1c
    • fat mass
    • Triglyceride in men
  • Androgens prevents visceral fat accumulation and improves insulin sensitivity [51]
  • testosterone in elderly patients with coronary heart failure improving
    • Functional capacity
    • Heart rate
    • Muscle strength
    • Glucose metabolism [69]

Testosterone teraphy

  • Intramuscular
    • Every 3–12 weeks
  • Buccal
  • Transdermal
    • Daily administration
  • Oral testosterone and 17-alpha-alkylated androgen preparations
    • Not recommended
    • Liver toxicity
    • Variable clinical response
  • 17 randomised clinical trials (RCTs)- 656 men (mean age 57.5 years)
    • testosterone therapy in men with a total testosterone concentration <12 nmol/l:
      • Moderately improved:
        • Sexual symptoms
        • Sexual function
    • Had no such effect in eugonadal men
  • Positive effect of testosterone therapy in hypogonadal men with depression
  • Increase in physical function in men
    • Aged 75 or greater
    • With two or more Fried frailty criteria
    • 10 mg/day improved muscle strength
  • Supra-physiological dose
    • Greater incidence of cardiovascular-related events
  • Improves lumbar Bone Mass Density by 8%
  • Suppression of hepcidin
    • Increases haemoglobin levels
      • Cca 1 g/dl
      • Haematocrit by ~3%
      • >3-fold risk of erythrocytosis [52]
  • Increases prostate-specific antigen levels
    • Tends to increase the risk of prostate biopsy [52]
    • no increased risk of prostate cancer
    • Continuing caution is required
      • Androgens may have a long latency in promoting the growth of pre-existing prostate cancer
  • Observational studies and a meta-analysis
    • Associations between testosterone therapy and a 30–54% increased risk of cardiovascular-related events
  • FDA: all these studies had significant limitations
    • Currently there is insufficient evidence for an association
    • Make clear that a low testosterone level due to ageing is not an indication for testosterone therapy
    • Cardiovascular safety monitoring of testosterone therapy in older men is required [52]

Contraindications to testosterone therapy

  • Erythrocytosis (haematocrit >52%)
  • Prostate cancer
  • Breast cancer
  • Untreated obstructive sleep apnoea
  • Uncontrolled heart failure
  • Severe lower urinary tract symptoms
    • International Prostate Symptom Score >19
  • Desire for fertility





Androgen excess In women

  • Hyperandrogenism promotes insulin resistance in women
    • Predisposes to T2D in women
    • “diabetes in bearded women” by Achard and Thiers in 1921 [51]
  • no effect on body weight in female mice
  • Low concentration of Sex-Hormone Binding Globulin (SHBG)
    • Increases free testosterone
    • Strong independent risk factor for the development of T2D [51]
  • Postmenopausal women with impaired glucose tolerance
    • Have higher androgen activity than women with normal glucose tolerance [51]
  • Androgen activity correlates with
    • The degree of glucose intolerance [51]
  • Higher levels of free testosterone and lower levels of SHBG
    • Repeatedly associated with
      • Glucose intolerance
      • Insulin resistance in women [51]
  • High free testosterone levels are associated with
    • Higher risk of T2D in women [51]
  • Estradiol levels
    • Were also elevated among postmenopausal women with diabetes
    • estrogen excess could also have played a role in T2D risk [51]
  • Postmenopausal women, higher plasma levels of estradiol and testosterone
    • Were strongly and prospectively related to increased risk of developing T2D [51]
  • Metabolic response of androgen-exposed women during hyperglycemic and euglycemic-hyperinsulinemic clamps
    • High testosterone levels produce insulin resistance
      • By decreasing insulin-stimulated whole body glucose uptake in healthy pre- and post-menopausal women
      • Hepatic insulin resistance remained unchanged
      • Role for skeletal muscle in insulin resistance
        • Fiber type switch na pomalá vlákna
          • Confirmed in studies of female rodents [51]
  • Insulin sensitivity improves
    • When hyperandrogenism is reversed with anti-androgen therapy
    • In association with weight loss [51]
  • Androgen excess alone may be instrumental in insulin resistance
    • Treatment with AR antagonists
    • Suppression of ovarian androgen production with GnRH analogues in hyperandrogenic women
      • Does not always improve insulin resistance
        • Excess androgens in women may not be the cause, just an aggravating factor [51]
  • Increases visceral adiposity in females [51]
  • Women with chronic androgen excess
    • Plasma testosterone is positively correlated with
      • Waist circumference
      • Index of visceral obesity [51]
    • Androgen excess might has masculinized the function of female adipose tissue [51]
  • Female mice exposed to the non-aromatizable androgen receptor agonist DHT
    • DHT prevents leptin from activating brown adipose tissue (BAT) thermogenesis
      • Reduced energy expenditure
      • Visceral obesity [51]
    • Decreased hypothalamic proopiomelanocortin (pomc) expression
    • Decreased POMC neuronal innervations into dorsomedial hypothalamus (DMH)
      • Visceral adiposity in hyperandrogenic females could have a central origin [51]
  • Androgen-induced visceral fat distribution and accumulation
    • Alteration of the melanocortin system between the ARC and DMH. [51]
  • Hyperandrogenism predisposes to ß-cell dysfunction in females
    • Various degrees of pancreatic ß-cell dysfunction [51]
  • Functional hyperandrogenism
    • Significantly higher basal insulin secretory rates
    • Attenuated post-prandial insulin secretory responses [51]
  • Women with hyperandrogenism
    • ß-cell hyperfunction
    • May predispose to secondary ß-cell failure [51]
  • Female mice
    • testosterone accelerates hyperglycemic decompensation in experimental models of insulin-dependent diabetes [51]
  • Excess testosterone
    • Induces systemic oxidative stress in female mice
  • Excess AR activation in ß-cells (and/or other tissues)
    • Predispose to the ß-cell dysfunction
    • Could be a direct islet effect [51]
  • testosterone infusion in healthy women
    • Does not produce ß-cell dysfunction [51]
  • Excess testosterone
    • Predispose ß-cell failure through the cumulative action of various ß-cell stresses [51]
  • Androgen excess-induced T2D
    • Was not observed in female ßARKO-/- mice
      • At least partially mediated via excess AR activation in ß-cells [51]






Antidepresiva

Tricyklická antidepresiva

  • Amitryptyline - jeden z nejobezitogennějších TAD
  • Nortriptyline (Weber et al., 2000)
  • Doxepin (Feighner et al., 1986) [1]

Selective serotonin reuptake inhibitors (SSRIs)

  • Paroxetine appears to be more likely to cause weight gain than other agents (Sussman et al., 2001) [1]
  • Weight gain in humans
  • Weight loss and reduced food intake in animals (Konkle et al., 2003) [1]
  • SSRIs
    • Associated with greater initial weight loss than nefazodone during acute treatment (Sussman et al., 2001) [1]
    • Long-term treatment SSRI-treated patients gained weight compared to nefazodone-treated [1]
    • Imipramine produced greater weight gain than did nefazodone during both the acute treatment phase and long-term treatment [1]

Monammine oxidase inhibitors


Atypical antidepressants

  • Buproprion
    • May be associated with weight loss (Croft et al., 2002) [1]
  • Nefazodone
    • Reportedly weight neutral (Sussman et al., 2001)
    • Appear to cause less weight gain in the long term [1]

Lithium

  • Přibírání váhy occurring in one third to two thirds of patients (Garland et al., 1988; Baptista et al., 1995) [1]

Antihistamines


Antipsychotika

Olanzapine

  • Olanzapine to ziprasidone
    • Lost weight when switched to ziprasidone
    • Improvements in lipid profile and glucose tolerance [1]

Chlomipramine

  • Weight gain and increased food intake in humans
  • Decreases food intake in animals (Calegari et al., 2007) [1]

Clozapine

  • Hyperphagia and weight gain in humans [1]
  • Increase in triglyceride
  • 37% increase in the incidence of type 2 diabetes over the 5-year period of observation (Henderson et al., 2000) [1]

Thioridazine/mesoridazine


Ziprasidone

  • Mnohem menší nárůst váhy než Clonazapin [1]

Risperidone

  • Produced less weight gain than did sertindole, olanzapine, or clozapine [1]

Sertindole


2-arachidonoylglycerol

  • Kanabinoid

Inhibice aromatázy

  • Catalyzes the conversion of androgen to estrogen
  • Mice with knocked out aromatase (ARKO) became obese when fed the same amounts as normal mice [2]

Avy mutation (Agouti mice)

  • Ectopic expression of agouti protein
    • Paracrine signaling molecule
    • Normally regulates the production of yellow pigment in fur
    • Binds antagonistically to the melanocortin 4 receptor in the hypothalamus
      • Inducing hyperphagic obesity (Wolff et al., 1999)[1]
  • Epigenetic metastability of the Avy locus
    • Genetically identical Avy/a mice vary dramatically in the degree of DNA methylation at Avy
      • Také potom i v coat color and adult adiposity (Wolff et al., 1999) [1]

Bariatrická redukce hmotnosti před otěhotněním

  • Children born after maternal weight loss
    • Lower risk for obesity than do their siblings born before maternal weight loss (Kral et al., 2006)[1]
    • “metabolic imprinting” of body weight regulation (Waterland and Garza, 1999; Waterland, 2005) [1]


11beta -hydroxysteroid dehydrogenase type 1 (11 beta HSD1)

  • Regenerates active cortisol from inert cortisone in adipose tissue
  • Elevated adipose tissue 11 beta HSD1 activity
    • Observed in obese humans and rodents [63]
  • Mice engineered to selectively over-express 11betaHSD1 in adipose tissue develop visceral obesity and metabolic syndrome6, whereas mice lacking 11betaHSD1 resist glucose intolerance, insulin resistance and hyperlipidemia on high-fat diet7. In humans, 11betaHSD1 inhibition has analogous effects8.
  • Potential mechanism by which estrogens acting via ER beta
    • May enhance local glucocorticoid action in adipose tissue of postmenopausal women
      • Involving up-regulation of adipose 11 beta HSD1 expression
        • Association was greatest in adipose tissue from postmenopausal women
    • Direct effect of selectively activating ER beta on adipocyte 11 beta HSD1 expression and activity was demonstrated in vitro [63]
  • Postmenopausal women
    • Major source of estrogens is local aromatase expression in the adipose tissue
      • Increases with age
    • Adipose 11betaHSD1 may be increased by local estrogens acting via ERbeta
      • Resulting in increased levels of active glucocorticoids in adipose tissue
        • Associated with obesity [63]
  • ERbeta mRNA levels
    • Two-fold higher in subcutaneous adipose tissue from postmenopausal women
    • Compared to premenopausal women
    • Expression of this receptor is strongly correlated with adipose expression of 11 beta HSD1 [63]
  • Aromatase promoter activity is driven by glucocorticoids
    • Increased 11betaHSD1 activity in adipose tissue
      • Will further amplify this process [63]
  • 11betaHSD1 activity
    • Increased in adipose tissue of even moderately obese women
    • Higher expression of 11betaHSD1 in the subcutaneous depot than other depots
      • Appears to be more predictive for obesity and metabolic parameters
      • Correlates with measures of central fat accumulation
      • Independent predictor for central fat accumulation
      • Important role of the 11betaHSD1 enzyme in subcutaneous adipose tissue [63]







Bisphenol A (BPA)

  • High production volume
  • Potential for widespread environmental contamination
  • Numerous studies have now shown an association of BPA exposure with increased body weight and adiposity
    • Sex specific
    • +body weights of pups obtained from moms fed BPA in their diets during pregnancy
      • Doses were low and were considered “ecologically relevant” at 1 µg BPA/kg diet (1 ppb) [69]

Role for this chemical in the development of obesity

  • BPA causes 3T3-L1 cells (mouse fibroblast cells that can differentiate into adipocytes) to increase differentiation
  • In combination with insulin, accelerates adipocyte formation
  • Low doses of BPA, similar to diethylstilbestrol
    • Impair calcium signaling in pancreatic cells
    • Disrupt beta cell function
    • Cause insulin resistance
  • Low environmentally relevant doses of BPA have also been reported to
    • Inhibit adiponectin
    • Stimulate the release of inflammatory adipokines
      • Interleukin-6 (IL-6)
      • Tumor necrosis factor-alpha
        • From human adipose tissue [69]
  • BPA is involved in obesity and the related metabolic syndrome
  • Detected at higher concentrations in both nonobese and obese women with polycystic ovarian syndrome
    • Than in nonobese healthy women [69]

Obezitogenní

  • Increase fat cell numbers or sizes [53]
  • Increases expression of FABP4 and CD36 [53]
    • Involved in lipid metabolism [53]
  • BPA exposure during adipocyte differentiation
    • Affects gene expression
    • Modulates adipose tissue functions:
      • PPAR
      • C/EBP
      • LPL
      • GLUT4
      • CYP19 [57]
      • GPAT
      • DGAT
      • Leptin (OB) (Vom Saal et al. 2012, Boucher et al. 2014, Ohlstein et al. 2014) [57]
  • Increases lipoprotein lipase gene expression
    • Tím i enzymatic activity
      • Leads to triacylglycerol accumulation (Masuno et al. 2002) [57]
  • Increase glucose transporter GLUT4 levels
    • Alter glucose uptake (Masuno et al. 2002, Sakurai et al. 2004)
  • Up-regulation of leptin mRNA levels (Angle et al. 2013) [57]
    • Jako důkaz většího obsahu tuku v tukové tkáni

FABP4

  • Produced in adipocytes
  • Fatty acid uptake and metabolism
  • Important contributor to metabolic dysfunction in obesity-induced chronic inflammation and dyslipidemia (Hardaway & Podgorski 2013)
  • Elevated FABP4 plasma levels
    • Associated with metabolic syndrome (Xu et al. 2007)
    • Obesogenic role for BPA
  • BPA Up-regulation of FABP4 and CD36
    • Significant increase in intracellular lipid droplets and in triglyceride concentration
      • BPA affects adipocyte lipid storage which leads to cellular hypertrophy
        • Results in a resistin secretion increase
        • Decrease in adiponectin production in vitro
          • (C Menale, A Grandone, C Nicolucci, G Cirillo, S Crispi, A Di Sessa, S Rossi, D G Mita, L Perrone, E M Del Giudice, N Diano, unpublished observations)
    • Might impair glucose metabolism
      • Confirmed by preliminary experiments performed in a mouse model (C Menale, personal communication)
    • Might increase the oxidative stress of hypertrophic adipocytes
    • Might contribute to the inflammation and dysregulation of free fatty acid efflux (Zha & Zhou 2012)

PC1/3

  • Cleaves pro-insulin to produce active insulin
  • Mutations of or deficiencies in PC1/3
    • Cause early obesity (Creemers et al. 2012, Turpeinen et al. 2013)
  • Deficiency of PCSK1
    • Leads to serious multi-hormonal disorder marked by early-onset obesity (Jackson et al. 1997) [57]

BPA mediates adipogenesis through an ER-dependent pathway gen expression

  • 1. signif. elevace exprese adipogennních genů již 7. den po oš. BPA: [53]
    • Mid-stage adipogenesis [53]
      • C/EBP [53]
    • Late adipogenic genes [53]
      • IGF1 [53]
      • LPL [53]
        • The greatest induction !!! [53]
    • Master transcriptional regulator of adipogenesis [53]
      • PPAR [53]
  • Upon treatment with the ER antagonist ICI 182 780
    • The effect of BPA on adipogenic differentiation was blocked [53]

  • Prenatal exposure to BPA in rodents
    • Increased white adipose depots
    • Increased expression of C/EBP?, PPAR?, and LPL [57]
  • Induction of DLK and IGF1 mRNA transcripts
    • DLK expression has been linked to adipogenesis
      • Target of PPAR transcriptional activity (Couture & Blouin 2011) [57]
  • IGF1 has been associated with obesity, insulin resistance, and adipogenesis (De Pergola & Silvestris 2013, Xie & Wang 2013) [57]

  • In mouse 3T3-L1 cells BPA increased
    • Lipoprotein lipase (LPL) activity
    • Triacylglycerol accumulation
    • Presence of larger lipid droplets in the differentiated cells [68]
  • Insulin and BPA interacted synergistically to further accelerate these processes
  • BPA also stimulated an
    • Increase in the glucose transporter GLUT4
    • Glucose uptake into 3T3-F442A adipocytes [68]
  • Up-regulation of GLUT4
    • Increased basal and insulin-induced glucose uptake into adipocytes



Koncentrace BPA

  • BPA has a maximal effect at a concentration of 1 µM [57]
  • Significant increase in adipogenesis in ASCs treated for 14 days at levels as low as 100 pM was observed
  • Average BPA serum levels
    • Between 1 and 20 nM [57]
  • With BPA showing activity in cellular assays as low at 1 pM to 1 nM
  • Robust response to BPA at 21 days
  • Substantial increase in transcriptional activity at day 7 was observed
  • Increased adipogenesis at 14 days in response to lower concentrations of BPA was noted [57]
  • Even low-level exposure to BPA can expedite differentiation of ASCs into a mature adipocytes [57]

  • Maximal effect at a concentration of 1 µM [68]
  • Observed cell death at a concentration of 10 µM [68]

Prozánětlivý

  • Increases the expression of pro-inflammatory cytokines [53]

CCL20

  • Gen pro cytokine
  • Hldina v krvi directly correlated with BMI (Hashimoto et al. 2006, Duffaut et al. 2009, Villaret et al. 2010) [53]
  • Elevated serum CCL13 and CCL20 concentrations [53]
    • In overweight subjects during chronic inflammation [53]
  • IL18 and IL1B [53]
    • Regulators of inflammatory responses

Diabetogenní

  • Decreases the expression of PCSK1 [53]
    • Involved in insulin production [53]
  • Involved in the onset of metabolic dysfunction [53]
  • Reduced insulin-stimulated tyrosine phosphorylation of insulin receptors
    • In adult adipocytes treated with BPA [53]
  • Reduction of insulin downstream signaling [53]
  • Associations between serum and urinary concentrations of persistent organic pollutants and diabetes have been described
  • Women with Polycystic Ovary Syndrome (PCOS)
    • Insulin resistance
    • Low-grade chronic inflammation
    • Elevated serum BPA levels [59]

BPA exposure

  • Cultured adipose cells derived from human subcutaneous tissue
  • 3T3-L1 adipocytes
  • Impaired
    • Insulin sensitivity
    • Glucose utilization
  • Enhanced
    • Release of pro-inflammatory compounds
      • Even in the absence of major derangement of adipocyte differentiation [59]

  • Nanomolar BPA concentrations [59]
    • May induce an inflammation-like response in human adipocytes [59]
    • Increases the release of IL-6 and IFN [59]
    • Aktivace JNK, JAK/STAT and NF-kB pathways [59]
  • Binds G protein-coupled receptor 30 (GPR30)
    • Novel non-classical membrane ER
    • Might induce biological effects in different cell types, including adipocytes [59]

  • BPA-treated adipocytes were less sensitive to insulin in terms of glucose utilization
    • Effect was already detectable upon treatment of the cells with 1 nM BPA [59]
  • BPA stimulated an increase in GLUT4 and glucose uptake in adipocytic cell models
    • Required doses considerably higher than those found in human tissues [59]
  • Increased basal glucose utilization
    • Increased levels of GLUT1 [59]
  • BPA-induced insulin sensitivity
    • May contribute to worsen the pro-inflammatory profile [59]
  • Reduced insulin-stimulated tyrosine phosphorylation of insulin receptor
    • Reduction of downstream signalling
      • Can be responsible for a worsening in insulin signalling via PKB/Akt and ERK
        • Reduction in insulin sensitivity in fat tissue [59]
  • Insulin suppresses the inflammatory process (in BPA treated adipocytes)
    • Preventing hyperglycemia [59]
    • Modulating key inflammatory molecules [59]
  • Decrease of leptin levels observed in BPA-treated adipocytes
    • May be due to reduced insulin promotion of leptin gene expression [59]
  • Inhibition of JNK activity
    • Almost completely restored insulin receptor signalling
    • Largely rescued insulin-stimulated glucose utilization in BPA-treated adipocytes [59]
    • Suggesting a primary involvement of inflammatory factors [59]
  • Exposure to BPA
    • Impairs insulin sensitivity
    • Induces the release of inflammatory factors in adipocytes [59]
      • One possible mechanism
        • BPA activates JNK, via TLRs or ERs [59]
          • May directly impair insulin action [59]
    • Release of IL-6 and IFN
      • Contribute to JNK activation in the adipocytes
        • Down-regulate insulin-stimulated glucose uptake [59]


PCSK1

  • Encodes pro-protein convertase subtilisin/kexin type 1 (PC1/3) [53]
  • Pro-insulin-processing enzyme
  • Regulates insulin biosynthesis
  • BPA effectively impairs active insulin production [53]
    • Its decrease is related to PCSK1 mRNA down-regulation [53]
    • PCSK1 could be considered a new player that is involved in the endocrine disruption that is caused by BPA
      • Key role in the deregulation of insulin biosynthesis [53]
    • BPA exposure in the mouse impairs glucose tolerance by compromising insulin production and/or secretion

CD36

  • Integral membrane protein that binds oxidized lipoproteins and lipids (Endemann et al. 1993) [53]
  • Key role in fatty acid and glucose metabolism [53]
    • Dysregulation in glucose intolerance and diabetes (Hajri et al. 2002, Rac et al. 2007) [53]
  • CD36 null mice [53]
    • Display enhanced insulin responsiveness [53]
    • Associated with a reduction in fat deposition (Hajri et al. 2002) [53]

IL1B [53]

  • Associated with insulin resistance and type 2 diabetes (Tack et al. 2012) [53]
  • Its inhibition reduces hyperglycemic inflammation in obese mice (Owyang et al. 2010) [53]


  • Low doses of BPA
    • Stimulated rapid secretion of insulin in mouse pancreatic ß cells in primary culture
      • Through a non-classical, non-genomic estrogen-response system
      • Magnitude of the response was the same at equal doses of BPA and estradiol [68]
  • Prolonged exposure to a low oral dose of BPA (10 µg/kg/day)
    • Stimulation of insulin secretion in adult mice
      • Mediated by the classical nuclear estrogen receptors [68]
    • Later was followed by insulin resistance [68]

Děti

  • Higher and more dangerous in infants and children
    • Can lead to the onset of several diseases [53]
      • Cancer [53]
      • Endometriosis [53]
      • Birth defects [53]
      • Developmental and neuronal disorders (Rochester 2013, Delclos et al. 2014) [53]
  • Associated with obesity and metabolic disorders (Rochester 2013, Lakind et al. 2014)
    • Specifically in children (Trasande et al. 2012, Lee et al. 2013, Nicolucci et al. 2013) [53]
  • Environmentally relevant BPA concentrations in adipocytes from children [53]
    • Increase the expression and the enzymatic activity of 11ß-hydroxysteroid dehydrogenase type 1 ::53:---key enzyme in adipocyte differentiation and lipid synthesis !!!
      • Stimulate preadipocyte differentiation and adipogenesis
        • Can thus promote obesity in childhood [53]
  • Non-linear effects during childhood [53]

  • Exposure to BPA just prior to puberty
    • Increase body weight

Hormonální dirupce

  • Endocrine disruptor
    • Activation of estrogen receptors alfa and ß (ERß) (Wozniak et al. 2005, Welshons et al. 2006, Le et al. 2008, Kim et al. 2012, Li et al. 2012, Chen Zee et al. 2013) [57]
  • Competing with endogenous hormones [53]
  • estrogen-like properties [53]
    • Low environmentally doses - can act as an estrogen antagonist [53]
    • Non-classical ER pathways (Li et al. 2012, Boucher et al. 2014) [53]
  • Increases in weight and size of the prostate gland in male offspring of treated mice
  • Decreases in sperm efficiency in young mice [88]
  • Disrupting effects on the: [53]
    • Classical nuclear receptors estrogen receptors alpha and beta (ER alfa and ER beta) [53]
    • Non-classical membrane estrogen receptor (ncmER) [53]
    • estrogen-related receptor gamma (ERR gamma) [53]
    • G protein-coupled receptor 30 (GPR30) [53]
    • Aryl hydrocarbon receptor (AhR) (Hugo et al. 2008, Alonso-Magdalena et al. 2012) [53]

Animal models, BPA has been shown to disrupt:

  • Thyroid hormones [53]
  • Estrogens [53]
  • testosterone [53]
  • Corticosteroids [53]
  • Growth hormone [53]
  • Leptin [53]
  • Alter adipogenesis [53]
  • Beta-cell and endocrine pancreas function [53]
  • Inflammation [53]
  • Insulin sensitivity [53]
  • Found to be oestrogenic in the MCF-7 human breast cancer cell culture in 1993 (Krishnan et al., 1993)
    • Concentrations as low as 2-5 ppb (2-5 µg/l)
  • Can also act as an antiandrogen
    • Blocking the action of dihydrotestosterone in a yeast screen containing a human androgen receptor (Sohoni and Sumpter, 1998)
      • Cca as potent as flutamide, a well known anti-androgen
  • Liquor containing bisphenol-A obtained from tinned vegetables
    • Found to be oestrogenic to human breast cancer cells
    • Identical effects to oestradiol on rat uterus and vagina
  • Exposure of developing male mice
    • Enlarge their prostate glands
  • Female mice exposed in the womb to low doses of bisphenol a (2.4 micro-g per kg per day to the mother)
    • Significantly reduced delay between vaginal opening and first vaginal oestrus (Howdeshell et al., 1999)
  • Methylation sensitive promoter
    • Genistein (increased methylation)
    • bisphenol A (decreased methylation)
      • Predicted an adult phenotype of yellow coat color, diabetes, tumors and obesity [68]
  • Coat color
  • Obesity in mice [68]
  • “fetal estrogenization syndrome” [68]
[68]
  • Interference with the production and signaling of sex hormones [92]
    • Led to neurological impairment [92]
    • Synapse formation during development is regulated by estrogen and androgens [92]
      • Levels deemed safe by the US Environment Protection Agency [92]
        • Completely abolish the response of synapses to estrogen in the prefrontal cortex and hippocampus [92]
  • Metabolic syndrome
  • Obesity
  • Non-insulin-dependent diabetes mellitus
  • Allergies and asthma
  • ADHD, autism, cognitive decline, memory impairment
  • Depression, and anxiety
  • Accumulate in fat
    • With 50% of breast adipose tissue from women containing BPA (Fernandez et al. 2007) [57]
%- Increased gut serotonin production in response to bisphenol A structural analogs may contribute to their obesogenic effects
  • Maternal exposure
  • Synthetic estrogen and ubiquitous industrial contaminant
  • Inducing DNA hypomethylation at Avy and another metastable epiallele, CabpIAP (Dolinoy et al., 2007) [1]


Borna Disease virus

Potkani

  • Cause obesity in rats (Gosztonyi et al 1995) [1]
  • Damaging the hypothalamus [1]
  • Neuroendocrine dysregulations (Herden et al 2000) [1]

Canine distemper virus (CDV)

  • Obesity promoting virus (Lyons et al 1982) [1]

Myši

  • Obesity develops after acute infection of mice when no virus is detectable [1]
    • “hit and run” (Bernard et al 1999; Nevels et al 2001) [1]
  • Decreases levels of melanin concentrating hormone (Veraeten et al 2001) [1]
  • Down-regulates leptin receptors in the hypothalamus (Bernard et al 1999) [1]

The C/EBP family

  • C/EBP alpha, beta, gamma, delta, omega
    • Recognizes a common DNA-binding element
    • Tissue-specific expression patterns
  • C/EBP beta and C/EBP omega
    • Expressed before than C/EBP alpha
    • Activate C/EBP alpha
  • PPAR gamma and C/EBP aplpha
    • Induce the differentiation into adipocytes

C/EBP binding domains

  • In promoters and activation together during adipogenesis
    • SCD1, aP2, S14, PEPCK, Glut4, UCP1, D2 (Christy et al., 1989) [80]

C/EBP alpha

  • Expressed in
    • Brown and white adipose tissues
    • Placenta
    • Liver
    • Master regulator of adipose tissue development
  • Development of brown adipose tissue during fetal life
    • C/EBP beta and C/EBP alpha
      • Increases precede C/EBP alpha expression (Manchado et al., 1994) [80]

C/EBP alpha overexpression

  • Induces differentiation of 3T3-L1 preadipocytes
  • As antimitotic inducing growth arrest (proteins GADD45 and p21) (Mandrup and Lane, 1997) [80]

C/EBP alpha in preadipocytes

  • Increases adipocyte-specific genes (aP2, Glut4)
  • Increases triglycerides accumulation (Lin and Lane, 1992; Mandrup and Lane, 1997) [80]

C/EBP alpha + PPAR alpha

  • Induce the differentiation into adipocytes

C/EBP alpha KO mice

  • Die shortly after birth due to
    • Hypoglycemia,
    • Defective hepatic glycogen storage and gluconeogenesis (Linhart et al., 2001) [80]
  • Had no WAT and little BAT
  • UCP1 mRNA was very low
    • C/EBP alpha is essential for the liver and adipose tissue developmental program
      • Adipogenesis was impaired and the mitochondria number and function reduced (Carmona et al., 2002)
  • Expression of PGC-1 and thyroid hormone receptors were delayed
  • BAT D2 activity and BAT T3 were very low
    • C/EBP alpha is critical for a correct BAT thyroidal status
    • BAT D2 is crucial for the differentiation and activity of fetal BAT
    • T3 is absolutely necessary for BAT function.

Neonatal hypothyroidism

  • Decreases C/EBP alpha and C/EBP beta expression in liver
    • But not in BAT (Menendez-Hurtado et al., 1997) [80]
  • In the PEPCK gene C/EBPs and TREs are related
    • Activation of C/EBPs is required for a functional TRE (Park et al., 1997) [80]

Cannabinoid systems


Carbamazepine [Tegretol, Tegretol XR , Equetro, Carbatrol]



CB1 receptory

  • In subcutaneous and visceral adipose tissue in humans
  • Proadipogenic and prolipogenic activity
  • Activating adipose tissue adipogenesis and lipogenesis in a depot-specific manner
    • Contributing to visceral obesity [13]

Regulace syntezy ceramidů

  • C16 and shorter chain ceramides
    • Antagonise the insulin receptor—PI3 kinase—Akt signalling pathway
    • Inhibit fat utilisation as an energy source via beta-oxidation

C24 ceramides

  • Synthesized by CerS2
  • Protect against insulin resistance

Synthesis of ceramides and other sphingolipids

  • Regulated by availability of fatty acyl-CoA substrates
    • Particularly palmitoyl-CoA derived from the fatty acid palmitate
  • ceramide synthesis may act as a direct metabolic sensor of fatty acid availability
    • Feeding back to regulate metabolic processes.

C18:011

  • CerS1 and its product C18 ceramide
    • Highly abundant in skeletal muscle (SkM)
  • Association between muscle C18:0 ceramide and impairments in insulin action
  • Circulating C18 ceramide
    • Significantly correlated with body mass index and visceral fat mass
  • C18 ceramide in SkM is positively correlated with visceral fat, as well as blood pressure

Selective inhibition of CerS5, CerS6, and/or CerS1

  • Would therefore be predicted to produce significant benefits for metabolic health

CerS2 inhibition

  • Would have detrimental effects

Isoform-specific CerS inhibitors

  • With sufficient potency, selectivity, and bioavailability for in vivo use have not yet been developed

CerS2, CerS1 activity

CerS inhibitor CerS1

  • CerS1 inhibition is shown to
    • Promote fatty acid oxidation in SkM
    • Reduce overall adiposity in mice fed a HFD.

Fingolimod (FTY720, Gilenya),

  • Analogue of the endogenous lipid sphingosine
  • Following its phosphorylation in vivo, Fingolimod is a potent agonist of sphingosine 1-phosphate receptors
  • Non-phosphorylated pro-drug also exhibits non-selective inhibition of ceramide synthases as an off-target effect

Non-phosphorylatable, chiral FTY720 analogue AAL(S)

  • Its benzyl tail derivative G024
  • Limited selectivity for CerS1 over other CerS isoforms
  • Degree of selectivity for CerS1 is poor
  • Do not selectively reduce C18 ceramide levels in cultured cells

(S)-2-amino-4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-methylbutan-1-ol (P053, [compound 2])

  • Potent and selective CerS1 inhibitor
  • The IC50 for inhibition of CerS1 with P053 was 0.5 microM
  • IC50’s for inhibition of CerS2, CerS4, CerS5, and CerS6 by P053
    • At least one order of magnitude higher than for CerS1, demonstrating strong selectivity for CerS1
  • The IC50 for P053 on CerS1 was similar to that of the potent but non-selective CerS inhibitor Fumonisin B1 (FB1)
  • Selectively reduces C18 sphingolipids in cultured cells
  • Formation of deuterated ceramide from deuterated (D7) dihydrosphingosine in cortical neuron cultures pre-treated for 2 h with P053.
  • www.nature.com/articles/s41467-018-05613-7
  • P053 selectively targets CerS1 in vivo
  • Pilot study, 7 days administration
    • Of P053 at 5 mg/kg/day
      • Reduced C18 ceramide levels in SkM by 31%,
    • 1 mg/kg/day had no effect
  • 5 mg/kg P053 daily for 4–6 weeks to mice fed either normal chow or a HFD
    • Only 18:1/18:0 and 18:2/18:0 ceramide were significantly reduced at P < 0.01
  • C18 is the dominant ceramide in SkM
    • P053 treatment reduced total ceramide content in this organ
  • Very long chain ceramides (C22:0, C24:0 and C24:1) were significantly increased by P053 treatment in the HFD group
  • Mean levels of 36:1 SM, which is derived from C18:0 ceramide, were 13% lower in P053-treated
    • Effect was not statistically significant
  • HexCer content was not significantly affected by P053 treatment
  • Increase in C24 ceramides was not associated with increased C24 ceramide synthase activity
    • Consequence of increased sphingoid base substrate availability due to the reduction in CerS1 activity
  • Sphingosine levels were increased 22%
    • As a result of CerS1 inhibition with P053 in mice fed a HFD
  • Dihydrosphingosine levels were not notably affected by P053 treatment
  • CerS1 inhibition selectively reduces C18 ceramide in SkM
  • www.nature.com/articles/s41467-018-05613-7
  • P053 treatment did not affect levels of common phospholipids from
    • The phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol families
  • Levels of most triacylglycerol (TAG) species were reduced by more than 50% in SkM
    • Total SkM TAG content was increased five-fold in mice on a HFD compared to a chow diet
      • Was 60% lower in the HFD + P053 group compared to the HFD vehicle group
  • P053 treatment did not affect SkM TAG levels in mice fed normal chow
  • TAGs are synthesized directly from diacylglycerol (DG)
    • DG levels were unaffected by P053 treatment
      • P053 does not directly inhibit TAG synthesis from DG.
  • CerS1 inhibition
    • Prevents fat deposition but not insulin resistance induced by a HFD
  • C18 ceramide content of SkM is positively correlated with visceral fat mass in humans
  • C24 ceramides were inversely correlated, with body fat
  • P053 treatment significantly reduced whole-body fat mass and the weight of individual white adipose depots in mice fed a HFD
  • Close association between excess adiposity and insulin resistance
    • HFD-fed mice displayed elevated fasting insulin + glucose intolerant
  • www.nature.com/articles/s41467-018-05613-7
  • CerS1 inhibition primes SkM to oxidise fatty acids
  • Lipid accumulation in tissues is determined by the balance between oxidation and storage
  • Lipotoxic effects of C16 ceramide
    • Partly due to inhibition of fatty acid beta-oxidation in liver and adipose tissue
  • HFD-fed mice treated with P053 displayed increased oxidation of 14C-palmitate
  • Fatty acid oxidation occurs in mitochondria and ceramides have been reported to directly influence
  • CerS1 inhibition
    • Overall increase in mitochondrial capacity
    • Significant increase in respiratory activity in the presence of complex I and IV substrates
    • Trend for an increase in complex II activity
    • Associated with significant up-regulation of genes encoding
      • mitochondrial-encoded (Co-2, Cytb, Atp6)
      • Nuclear-encoded (Ndufb5, Atp5o, Cycs, Cox5b) respiratory complex subunits
    • Increased activity of the TCA cycle enzyme citrate synthase—a commonly used marker of
      • mitochondrial content
      • Increased activity of the beta-oxidation enzyme betaHAD
  • Specific to muscle, with no increase in mitochondrial markers in liver
    • Where CerS1 and C18:0 ceramide are low
    • P053 had no significant effect on lipid levels.
  • CerS1 inhibition increases mitochondrial markers in SkM
  • www.nature.com/articles/s41467-018-05613-7
  • CerS1 inhibition does not affect mitochondrial markers in liver
  • Increased transcription of respiratory complex subunits suggested that P053 enhances mitochondrial biogenesis
  • AMP-activated protein kinase (AMPK) is an important regulator of mitochondrial biogenesis in muscle
    • Activity is influenced by intracellular ceramide levels
    • P053 treatment had no effect on phosphorylation of AMPK or its downstream substrate acetyl-CoA carboxylase (ACC)

Myriocin

  • CerS isoforms, particularly CerS4 and 5
  • Short-term infusion of LDL containing C24:0 ceramides in mice
    • Alter membrane C24:0 ceramide content in SkM
  • There was no effect of P053 on ceramide levels in the brain
    • Despite high CerS1 expression levels
  • Genetic ablation of CerS1
    • Causes neurodegeneration and cerebellar atrophy during development
  • Blocking total sphingolipid synthesis with myriocin
    • Protect against insulin resistance and hepatic steatosis in rodents
    • Genetic ablation of Cers5 and CerS6 in liver and adipose tissue too
  • CerS2, CerS5, and CerS6
    • CerS isoforms that are more highly expressed in liver and adipose tissue
    • Play a much more significant role than CerS1 in regulating glucose homoeostasis and insulin action
  • Chronic CerS1 inhibition priming SkM to metabolise fatty acids
  • Enhanced palmitate oxidation following CerS1 inhibition was associated with higher respiratory capacity, increased mitochondrial protein levels, and increased gene expression for respiratory complex subunits
  • Genetically enhancing fatty acid oxidation in SkM did not reduce adiposity through:
    • Deletion of acetyl-CoA carboxylase 2
    • Muscle-specific expression of carnitine palmitoyltransferase-1
  • Increased fatty acid oxidation was coupled with elevated markers of mitochondrial content and activity
    • Rate of palmitate oxidation in isolated SkM was directly comparable to its incorporation into TAG
  • Elevated expression of PGC-1alpha and other important transcriptional regulators of mitochondrial content and function
  • Loss of CerS2
    • Reduce respiratory enzyme activities
    • Increase mitochondrial oxidative stress
    • Attributed to elevated C16 ceramide
  • C18 ceramide behaves similarly to C16 ceramide in
    • Suppressing respiratory enzyme levels and fatty acid beta-oxidation
  • Exogenous CerS1 expression and a mitochondrial-targeted analogue of C18 ceramide
    • Promote mitophagy
  • Ceramides have also been shown to induce mitochondrial fission in SkM cells
    • Reducing their oxidative capacity
  • CerS1 inhibition
    • By lowering the overall ceramide content of SkM, boosts respiratory capacity via inhibition of fission.
  • Genetic ablation of the Drosophila CerS homologue Schlank
    • Results in the absence of fat pads
  • serine palmitoyltransferase inhibitor myriocin
    • Reduces adiposity and hepatic steatosis in rodents fed a HFD
  • CerS1 inhibition
    • Significantly impedes fat deposition
    • CerS1 is not expressed to a significant extent in adipose tissue or liver
  • C18 ceramide in SkM
    • Was positively correlated with visceral fat mass, blood pressure, and liver fat in humans
    • Identified a significant positive correlation between C18 ceramide in SkM and whole body fat mass in mice
  • P053 significantly
    • Reduced C18 ceramide in SkM
    • Without affecting ceramide levels in liver and adipose tissue
  • Inverse correlation of C24 ceramides with adipose tissue weight and % body fat was observed
  • Inhibition of CerS1 may therefore reduce adiposity
    • Directly by reducing C18 ceramide in SkM
    • Indirectly through the associated increase in C24 ceramide
  • www.nature.com/articles/s41467-018-05613-7

Chemical polutants

  • Chemical pollutants, are now considered contributing factors for insulin resistance
  • Most of chemical pollutants potentially accumulate into adipose tissue
  • “environmental obesogen hypothesis”
    • Associated to the adipose tissue inflammatory phenotype
      • Major contributing factor for the decreased insulin sensitivity [68]
  • Synthetic chemical lipophilic pollutants
    • Pesticides
    • Organophosphates
    • Polychlorinated bisphenyls
    • Phthalates
    • Solvents etc. [68]
  • Diet, the air and the ground
  • Those which are resistant to biological and chemical degradation
    • Persistent Organic Pollutants(POPs) [68]
      • Most of them also classified as endocrine disruptors [68]


Chlamydophila pneumoniae

  • Association with higher BMI in humans (Ekesbo et al 2000; Dart et al 2002) [1]
    • Others found no association (Blanc et al 2004; Falk et al 2002; Muller et al 2003) [1]
  • Antibody positive subjects
    • Older
    • Lower socioeconomic status
    • Higher fasting insulin levels [1]
  • Is obesity is associated with impaired immune function ? (Marti et al 2001) [1]

Contraceptives


Cushing's syndrome

Dexamethasone

  • Preadipocyte differentiation induced using
    • Dexamethasone
    • IBMX
      • Agent that increase cAMP levels [80]

Diethylstilbestrol

  • Developmental exposure is associated with obesity or overweight and adipogenesis
  • Synthetic nonsteroidal chemical with estrogenic activity
  • 1950s–1960s as a feed additive
    • To enhance weight gain in cattle and poultry
  • 1940s–1970s widespread clinical use
    • To prevent miscarriage and other complications of pregnancy
  • 1971
    • Prenatal diethylstilbestrol treatment associated with a rare form of
      • Reproductive tract cancer
      • Vaginal clear cell adenocarcinoma (<0.1%) of adolescent daughters of women who had taken the drug while pregnant
  • More frequent benign reproductive tract problems
    • In >95% of the diethylstilbestrol-exposed daughters
      • Reproductive tract malformation
      • Dysfunction
      • Poor pregnancy outcome
      • Immune system disorders
  • Prenatally diethylstilbestrol-exposed men
    • Range of reproductive tract abnormalities
      • Hypospadias, microphallus, retained testes
      • Increased genital-urinary inflammation
      • Increased incidence in prostatic and testicular cancers
  • Cross the placenta and to induce a direct carcinogenic effect on fetus
  • Diethylstilbestrol-exposed women
    • Higher incidence of breast cancer as they age
  • Another generation may be at risk of developing health problems
  • Obesity and overweight
    • Suggested that exposure to EDCs during critical stages of adipogenesis is contributing to the obesity epidemic
    • Experimental animal studies support the idea of involvement of EDCs in obesity

Dioctanoylglycerol

  • Activates ERK
    • Increases lipolysis [13]

Direct uptake of TAG

  • Associated with lipoproteins coming from the circulation
  • Hydrolized by lipoprotein lipase in non-esterified free fatty acids
  • Transported into and in the cells by a family of fatty acid binding protein
    • FABP, FAT, FATP, aP2 [78]

Boredom, sadness, stress, or anger

  • Eat excessively in response to emotions
  • Most overweight people have no more psychological disturbances than normal weight people
  • Serious weight problems
    • 30% difficulties with binge eating

The Endocannabinoid System

  • Chronically activated in obese individuals
  • Dysregulation associated with visceral obesity rather than with overall adiposity

Endogenous agonists of the endocannabinoid receptor type 1 (CB1)



Endocannabinoid System

  • Endogenous agonists of the endocannabinoid receptor type 1 (CB1)
  • Most studied endocannabinoids
    • Anandamide
    • 2-arachidonoylglycerol [13]
  • Chronically activated in obese individuals
  • Interacts with several major players in the multiple cascades of metabolic regulation
  • CB1 receptor antagonists
    • Decrease food intake
    • Induce significant weight loss
    • Successfully address several metabolic alterations associated with obesity [13]
  • Side effects of the first generation compounds
    • Anxiety and depression [13]
  • Dysregulation of the endocannabinoid system
    • Preferentially associated with visceral obesity [13]
  • Adipose tissue expresses CB1 receptors
  • Endocannabinoids
    • Detected in both subcutaneous and visceral adipose tissue in humans
    • Activating adipose tissue adipogenesis and lipogenesis in a depot-specific manner
      • Contributing to visceral obesity [13]
  • Peripheral overactivation of the system [13]

Endocrine disrupting chemicals (EDCs) - environmental obesogens

  • Many of the effects occur in response to low doses of hormones
    • Do not occur at much higher doses [68]
  • Opposite effects of low and high doses are observed
  • Traditional toxicological testing
    • Examination of a narrow range of very high doses
    • Based on a dose that was found to be acutely toxic [68]
  • Disruption of endocrine signaling systems by low doses
    • Lead eventually to obesity at the relatively low internal doses [68]

Estrogenic EDCs = selective estrogen receptor modulators (SERMs)

  • Have the capacity to bind to classical nuclear estrogen receptors (both the alpha and beta forms)
  • Initiate or inhibit transcription of estrogen-responsive genes
  • Gene-response profile is not identical to the response caused by an equal dose of estradiol
  • Specific responses caused by estrogenic EDCs and estradiol may vary between tissues
  • Can bind to non-classical estrogen receptors associated with the cell membrane
    • Rapid-response systems
      • Greatly amplify extracellular signals [68]

Typ I

  • Steroidní hormony
    • SERM

Typ II

  • Thyroid receptor (TR)
  • vitamin D rec. (VDR)
  • Receptory pro retinoidy (RXR)
  • Receptor pro aktivaci proliferátorů peroxizomů (PPAR)
  • Aryl hydrocarbon receptor (AhR)

Typ III

  • Funkce zatím neurčena

Endocrine disrupting chemicals (EDCs) - environmental obesogens

Typ I

  • Steroidní hormony

Typ II

  • Thyroid receptor (TR)
  • vitamin D rec. (VDR)
  • Receptory pro retinoidy (RXR)
  • Receptor pro aktivaci proliferátorů peroxizomů (PPAR)
  • Aryl hydrocarbon receptor (AhR)

Typ III

  • Funkce zatím neurčena

Mammalian embryonic development

  • Fetal epigenetic programming
  • Hormonal signals control
    • Timing of gene expression
    • Set the activity of genes
      • Functioning of organs
      • Homeostatic systems for the remainder of life (Newbold et al 2004) [1]

Organontin endocrine disruptors

  • Agricultural fungicides
  • Rodent repellents
  • Molluscicides
  • Antifouling paints for ships and fishing nets

Nuclear Receptors (NR) agnonists

  • High affinity agonists
    • PPAR-gamma [1]
    • Retinoic acid X receptor (RXR) (Kanayama et al 2005)[1]

Nuclear receptor antagonists

Environmental estrogens = anti-androgens (Sohoni et al 1998)

  • Estrogen a testosteron disruption
    • Permanent changes in reproductive organ development
    • Change in regulation of body fat and weight [1]
  • DDT

Bisphenol A - BPA

  • Monomer used in the manufacture of polycarbonate plastics and resins
  • Pregnancy - lactation
    • Increased body weight soon after birth and continued into adulthood
    • High dose (1.2 mg /kg body weigh/day) of BPA
      • Altered patterns of estrous cycle
      • Decreasing levels of plasma luteinizing hormone in adulthood [2]
      • Low reproductive activity in female
      • High increase of reproductive tract dysfunction in male and female [2]
  • BPA induced mitochondrial injury
    • DJ-1 plays a role in the prevention [2]

Butyl benzyl phthalate [1]

Diethylstilbestrol - DES

  • Developmental exposure to low dose
    • Decreased body weight gain
    • Elevated metabolic rate [2]

Soja estrogens

  • Neonatal exposure to soybean products enriched in phytoestrogens
    • Altered body weight, adiposity and adipokines in adult female mice [2]

Další přímé disruptory

Polybrominated diphenyl ether (PBDE)

Butyltins

  • Tributilin
  • Tetrabutilin

Dioxins

  • 1, 2, 3, 4, 6, 7, 8-heptachloro dibenzo-p-dioxin

Heavy metals

  • Cd
  • Hg
  • As
  • Pb
  • Mn

Organophosphates

Pesticides

  • Numerous pesticides affect hormone synthesis and/or metabolism [1]
    • Obzvláště lipofilní, resistant to metabolism [1]
    • Bioconcentrate up the food chain - stored in body fats [1]
      • Can be transferred to the developing offspring
        • Via the placenta
        • Via the egg [1]

Phthalates

  • Dibutyl phthalate
  • Butyl benzyl phthalate (BBP)
    • Decrease in maternal body weight gain and food consumption in pregnant rats
    • Decreases in the weighs of their male and female fetuses [2]

Solvents

Atrazine

Organochlorine pesticides

  • DDT
  • Lindane
  • Chlornan
  • Oxychlordan

Další

  • Lieldrin
  • Karbaryl
  • DDT a DDE
  • Dikofol
  • Dieldrin
  • Endosulfan
  • Mirex
  • Parathion
  • Toxaphen
  • Pyrethroid

Nepřímé disruptory

Inhibiting aromatases - P450 family members CYP19 and CYP3A1

  • Converze testosterone to estradiol
  • Supprese CYP19
    • PCBs 28 a 105
    • Aroclor 1221
  • Activace exprese CYP3A mRNA (interacted with PXR)
    • Methoxychlor
    • Benzophenone

Disrupt proper neuronal synapse formation

  • Affect release of brain-produced hormones that bind to nuclear receptors [1]

Olestra

  • Dietary fat substitute
  • Decreased Arochlor 1254 contamination
  • Facilitated weight loss in an obese diabetic male (Redgrave et al 2005) [1]

Herbicidy

  • Alachlor
  • Amitrol
  • Atrazin
  • Metribuzin
  • Nitrofen
  • Linuron

Fungicidy

  • Benomyl
  • Fenarimol
  • Maneb
  • Vinklozin
  • zinek
  • TBT

Průmyslové chemikálie

Detergenty (povrchově aktivní látky)

  • Alkylfenolethoxylát

Literatura:

[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.
[2] Regulation of Energy Metabolism Pathways by Estrogens and Estrogenic Chemicals and Potential Implications in Obesity Associated with Increased Exposure to Endocrine Disruptors. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2747085/?tool=pmcentrez >.

Endothelial cells of adipose tissue capillaries

  • Able to turn into pericytes
  • And then into either white and brown adipocytes [77]

Epigenetika

  • Chromatin conformation
  • Transcriptionally competent
  • Extra level of information above the DNA sequence information
  • Is replicated during cell division
    • Mitotic heritability
  • May also be meiotically heritable
    • Potential for transgenerational epigenetic inheritance
  • Environment can induce persistent epigenetic alterations [1]
  • Epigenetic dysregulation can cause obesity [1]


ER beta

  • Pro-adipogenic role for ERbeta
    • Supported by studies in knock-out mice
    • ERbeta knock-out (betaERKO) mice are normal weight [63]
  • Humans
    • Subjects with more ERbeta than ERalpha in omental adipose tissue
      • Had a greater degree of adiposity [63]
  • ER alpha knock-out (alphaERKO) and double knock-out (alpha/betaERKO) mice
    • Show marked obesity [63]
  • Alpha ERKO mice
    • Elevated 17beta-estradiol levels
      • Thus increasing ERbeta signalling
    • When ERbeta signalling is removed in alphaERKO by ovariectomy
      • fat-pad weights and adipocyte size decrease [63]
  • In vitro, the ERbeta agonist - DPN
    • Maximal up-regulation of 11betaHSD1 at 1-10nM in adipocytes [63]
  • 17beta-estradiol
    • Can activate the 11betaHSD1 promoter in transfected adipocytes [63]

  • Postmenopausal setting
    • Beneficial effects of activating ER alpha are diminished
      • Due to a decrease in circulating 17-beta-estradiol levels
    • May contribute to the increase in obesity [63]

Estrogen receptor alfa knocked out (alfa-ERKO) mice

  • Adipocyte hyperplasia/hypertrophy
  • Vzestup hmotnosti
  • Insulin resistance
  • Glucose intolerance [1]
  • Reduced energy expenditure in both sexes [2]
  • 10-fold increase in E2 [2]
  • Persistent / increased E2 signaling through ER-beta [2]
    • Obesity factor in alfa-ERKO mice ? [2]
  • Strong staining for ER-beta in adipose tissue [2]
  • Ovariectomized (Ovx) alfa-ERKO mice
    • Removing E2/ER-beta signaling in alfa-ERKO mice by ovariectomy
    • Poklesla hmotnost proti alfa-ERCO
      • 45% decreases in bodyweight and adipocyte circumference [2]
    • Nižší hladiny glukózy před i po gluk. inj. [2]s
    • Nižší hladiny inzulínu
    • E2 replacement (rušení účinků ovariektomie)
      • Zvýšila body weight na úroveň alfa-ERCO
        • O 16% tělesné hmotnosti [2]
      • Zvýšila hladiny glukózy před i po inj. glukózy i inzulínu [2]
      • Metabolické NÚ suplementace E2 menopauzálních žen s převahou ER-beta / mutacemi snižující funkci ER-alfa ???
      • Možnost využití anti-ER-beta v terapii lipedému ???
  • Expression of ER-alfa functional domain in plasma membrane in alfa-ERKO mice did not prevent from developing obesity [2]

Estrogen receptor beta knock out (beta-ERKO) mice

  • Insulin resistance
  • Impaired glucose tolerance (Heine et al 2000) [1]
  • no difference in brown adipose tissue (BAT) weight mice of all ages
  • WAT increased with advancing age in male mice (Heine et al 2000) [1]
  • Reduced energy expenditure rather than increased energy intake (Heine et al 2000) [1]
  • Some mutations in human ER-beta gene
    • Obese adolescents and women with bulimic disease [2]
  • Inhibitory effects of E2 on food intake and bodyweight blocked
    • By anti-sense oligonucleotides of ER-beta in brain
      • Not blocked by antisense of ER-alfa [2]

Deficiency or loss of estrogens

  • Adult animals gain bodyweight [1]
  • Oestrogen deficiency in males
    • Possibly responsible for body fat increase [54]
    • Reduced sexual function (Finkelstein et al., 2013) [54]

Ovariectomy

  • Ovariectatomied (Ovx) mice and Syrian hamster increases WAT [1]

Deficiency or loss of estrogens

  • Adult animals gain bodyweight [1]


Estrogens

  • Developmental exposure is associated with obesity or overweight and adipogenesis

Environmental estrogens = anti-androgens (Sohoni et al 1998)

  • Estrogen a testosteron disruption
    • Permanent changes in reproductive organ development
    • Change in regulation of body fat and weight [1]

DDT


Bisphenol A - BPA

  • Monomer used in the manufacture of polycarbonate plastics and resins
  • Pregnancy - lactation
    • Increased body weight soon after birth and continued into adulthood
    • High dose (1.2 mg /kg body weigh/day) of BPA
      • Altered patterns of estrous cycle
      • Decreasing levels of plasma luteinizing hormone in adulthood [2]
      • Low reproductive activity in female
      • High increase of reproductive tract dysfunction in male and female [2]
  • BPA induced mitochondrial injury
    • DJ-1 plays a role in the prevention [2]

Butyl benzyl phthalate [1]


Diethylstilbestrol - DES

  • Developmental exposure to low dose
    • Decreased body weight gain
    • Elevated metabolic rate [2]

Soja estrogens

  • Neonatal exposure to soybean products enriched in phytoestrogens
    • Altered body weight, adiposity and adipokines in adult female mice [2]

Eugregarinorida (Apicomplexa)

  • Non-invasive gregarine gut parasite

Dragonflies (Libellula pulchella)

  • Symptoms similar to human metabolic syndrome (Schilder et al 2007) [1]
    • Higher thoracic lipid accumulation [1]
    • Inability to oxidize fatty acids in muscle tissue [1]
    • Higher hemolyph carbohydrate concentrations [1]
    • Increased insulin resistance
    • Elevated markers of a chronic inflammatory state [1]
  • Factors secreted by the parasites were considered responsible for the phenomenon
    • Exact mechanism is unknown [1]

Fasn expression


Fatty acid synthase

  • Key lipogenic enzyme [70]

FGF10

  • Proposed as a mitogen for WAT
  • FGF10-/- mouse embryos the development of WAT is greatly impaired
    • Decreased proliferative activity of WAT
    • FGF10 and not C/EBPalpha is required for the proliferation of white preadipocytes (Asaki et al., 2004) [80]

Fruktóza

  • High-Fructose Corn Syrup Consumption (HFCS)
  • Ne ovoce jako samostatné jídlo
  • Vyšlechtěné druhy ovoce dnes mají mnohem vyšší obsah cukru než kdysi !
  • Fruktoza dělá také erektilní dysfunkci
    • Blok produkci NO
  • Vznik viscerálního tuku

Fruktozo-glukozový sirup

  • Z kukuřice až 80% fruktozy
    • Kontaminanty +
  • Cca 1 Američan vypije 70-120 g fruktozy denně

Follicle-stimulating hormone receptor

  • Adult knock out mice gain bodyweight [1]

FSH - Follicle-stimulating hormone

  • Glycoprotein hormone derived from the pituitary
  • Gonadal and germ cell development
  • Sex hormone production
  • Functionalities are dependent on the binding of FSH to cognate FSH receptors (FSHRs) in target organs
    • Ovary and the testis
  • Circulating FSH levels
    • Dramatic changes with age
      • Loss of negative feedback from
        • Inhibin
        • Androgens
        • Oestrogens
  • High circulating FSH levels
    • Diagnostic signs of menopause in females and males (Tajar et al., 2012)
  • FSHR expression
    • Gonads
    • Osteoclasts
      • Role of FSH in postmenopausal osteoporosis
    • Adipose tissue of chickens
      • Implicated in lipid biosynthesis (Cui et al., 2012).
  • High circulating FSH levels and
    • Increased body weight of Chinese males and females
      • FSHR might be expressed in human adipocytes [54]

Galanin

  • Pituitary-secreted peptide
  • Stimulate food intake (Kyrkouli et al., 1986) [1]
  • Galanin mRNA is increased in brains of sleep-deprived rats (Lu et al., 2005)
    • Hypothalamus (Fujihara et al., 2003; Toppila et al., 1995)[1]

Genetika

  • Obesity is a complex, multifactorial phenotype [1]
  • 11 human genes that cause monogenic obesity [1]
  • 52 genomic regions harboring quantitative trait loci associated with human obesity (Rankinen et al., 2006) [1]
  • More than 400 such sample associations have now been reported [1]
    • 22 genes supported by at least 5 studies (Rankinen et al 2006) [1]
  • Population genetic variations among people induce approximately 65% of the phenotypic variation among people in phenotypes like BMI (Segal et al 2002) [1]
  • Heritability of body fat in humans range from about 25 – 75% (Maes et al 1997; Segal et al 2002) [1]
  • More than 200 genes that regulate lipid droplet morphology have been identified in Drosophila [7]

INS - třídy alel kódující inzulín

  • Variable number of tandem repeats (VNTR) at the locus [1]

Class I VNTR allele

  • Predispose to childhood obesity
  • Only when inherited from the father (Le Stunff et al., 2001) [1]
  • When inherited from the mother, the allele is epigenetically silenced
    • Protection from the obesigenic effects of the class I VNTR polymorphism [1]


Leptin -LEP mutations

  • Monogenic obesity in humans (Rankinen et al., 2006) [1]
  • Promoters of LEP gene contain regions with a high density of CpG sites [1]
  • Cytosine methylation at such CpG islands functions to silence genomically imprinted alleles and genes on the inactive X chromosome [1]
  • Most promoter region CpG islands are unmethylated in normal tissues (Shen et al., 2007) [1]
  • LEP and POMC CpG islands exhibit tissue-specific methylation
    • Correlates with expression [1]
  • The LEP CpG island slightly hypomethylated in human adipose tissue DNA relative to peripheral blood DNA (Stoger, 2006)
    • Consistent with the adipocyte-specific expression of leptin [1]
  • More striking tissue-specific hypomethylation
    • Might be in isolated primary adipocytes
      • Most DNA in adipose tissue is derived from non-leptin-expressing stromal-vascular cells
      • Human pre-adipocytes (which do not express leptin) CpG islands are hypermethylated [1]
      • Leptin expression of differentiated adipocytes
        • Correlated with LEP CpG island hypomethylation (Melzner et al., 2002) [1]
  • “obesity genes” are regulated by epigenetic mechanisms [1]

Párování obézních mezi sebou

  • Mating of biologically related individuals [1]
  • Inbreeding may be considered an extreme form of assortative mating
    • Probability of increasing the genetic predisposition to obesity in the offspring of two obese parents could be very high [1]
  • Significant spousal similarities in BMI and triceps skinfold
    • Correlations did not increase with length of marriage duration. (Knuiman et al 1996) [1]

Prader Willi syndrome (PWS)

  • Hyperphagic obesity
  • Lack of paternal expression of genomically imprinted genes on chromosome 15q11-q13 [1]
  • Most PWS [1]
    • Paternal deletion [1]
  • Cca 25% of cases
    • Maternal uniparental disomy
      • Inheriting both copies of chromosome 15 from the mother (Goldstone, 2004)
        • no genetic lesion in these cases
        • Inappropriate epigenetic silencing of both copies of the 15q11-q13 region leads to obesity [1]

Proopiomelanocortin - POMC mutations

  • Monogenic obesity in humans (Rankinen et al., 2006) [1]
  • Epigenetická regulace transkripce [1]

Selekční výhoda pro rozmnožování

  • USA - individual’s BMI is significantly and positively related to the number of offspring that the individual has produced (Weng et al 2004; Bastian et al 2005; Rosenberg et al 2003) [1]
    • Min. 1 dítě between baseline measurement and the 4 years to follow-up
      • Gained more weight (~4.4 kg) than women s 0 dětmi (Rosenberg et al 2003) [1]
  • The magnitude of the associations of parity to overweight was greatest in
    • North Africa/West Asia
    • Latin America
    • Caribbean regions [1]
  • Positively correlated with levels of country development [1]
    • Effect of mild-to-moderate obesity on fecundity may be positive [1]
      • Obesity in women is associated with lower socioeconomic status (Lipowicz, 2003), which has been linked to producing more offspring (Salihu et al., 2004)[1]
      • Women that are too lean suffer impaired fertility (Frisch, 1987) [1]
  • V jiné studii korelovalo normální BMI v pubertě s vyšším počtem potomků [1]





Genetika

  • Obesity is a complex, multifactorial phenotype [1]
  • 11 human genes that cause monogenic obesity [1]
  • 52 genomic regions harboring quantitative trait loci associated with human obesity (Rankinen et al., 2006) [1]
  • More than 400 such sample associations have now been reported [1]
    • 22 genes supported by at least 5 studies (Rankinen et al 2006) [1]
  • Population genetic variations among people induce approximately 65% of the phenotypic variation among people in phenotypes like BMI (Segal et al 2002) [1]
  • Heritability of body fat in humans range from about 25 – 75% (Maes et al 1997; Segal et al 2002) [1]
  • More than 200 genes that regulate lipid droplet morphology have been identified in Drosophila [7]

Ghrelin

  • Gut-derived hormone
  • Released prior to feeding that stimulates hunger, feeding, and fat storage (van der Lely et al., 2004) [1]

De novo synthesis from glucose

  • Into the cell
  • Mainly via the insulin-sensitive glucose transporter isoform Glut 4
  • Glycerol-3-phosphate
  • Synthesis of pyruvate
    • Formation of acetyl-CoA
    • Transformation into malonyl CoA
      • Via acetyl-CoA carboxylase [78]
  • Fatty acid synthase to long chain fatty acids
    • Multienzyme complex [78]
  • Mainly under the control of insulin

Glukokortikoidy

  • Chronic glucocorticoid excess (e.g. in Cushing’s syndrome)
    • Causes obesity
    • Associated metabolic dysfunction
  • Plasma cortisol levels are not elevated in obesity
    • Selective increase in glucocorticoid regeneration in adipose tissue
      • Specifically, the microsomal enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1)
        • Catalyses the intracellular reactivation of cortisol from inert cortisone [63]

Oral contraceptives


High fat diet

  • Animals fed a high-fat diet for 8 months
    • Increased percentage of fat mass (FM)
    • + serum insulin-like growth factor-I (IGF-I)
    • + leptin levels
    • -percentage of fat-free mass (FFM)
    • -serum adiponectin levels [20]

Hormony

Ghrelin

  • Gut-derived hormone
  • Released prior to feeding that stimulates hunger, feeding, and fat storage (van der Lely et al., 2004) [1]

Leptin

  • Secreted from adipose cells
  • Attenuates food intake
  • Increases energy expenditure (Halaas et al., 1995) [1]
  • Decreases appetite [1]
  • Plasma maximum level midway through a normal nocturnal sleep period (Simon et al., 1998) [1]
  • Lower levels of plasma leptin related to sleep loss thus
    • Contribute to increased appetite [1]

Administration of leptin

  • In the neonatal period - or via the mother hlodavcům
    • Prevents the development of the metabolic phenotype and adiposity (Stocker et al 2004; Vickers et al 2005) [1]
    • Reversal of the changes in gene expression and methylation in liver tissue when examined as adults (Gluckman et al 2007c) [1]
    • May be acting by effects on neonatal food intake
    • Effects on hypothalamic maturation (Bouret et al 2004) [1]
      • Critical period ?? [1]
Spánek je důležitý - obzvláště u malých dětí i v prevenci obezity ap.

Galanin

  • Pituitary-secreted peptide
  • Stimulate food intake (Kyrkouli et al., 1986) [1]
  • Galanin mRNA is increased in brains of sleep-deprived rats (Lu et al., 2005)
    • Hypothalamus (Fujihara et al., 2003; Toppila et al., 1995)[1]

Orexin

  • In the lateral hypothalamus
  • Stimulates food intake as well
  • In rodents, orexin levels are increased by sleep deprivation
  • Decreased with recovery sleep (Pedrazzoli et al., 2004) [1]

Estrogeny

    • Endogenous estrogens
      • 17-beta-estradiol (E2) [2]
    • Environmental estrogenic EDCs
  • Estrogens regulated the body weight and energy metabolism in the brain
    • Similar to that of the leptin
  • Involved in the regulation of body weight and obesity

Ovariectomy

  • Ovariectatomied (Ovx) mice and Syrian hamster increases WAT [1]

Deficiency or loss of estrogens

  • Adult animals gain bodyweight [1]

Estrogen replacement therapy (ERT)

  • Decreases WAT (Wade et al 1985) [1]
  • Syrian hamsters with estrogens
    • Decreases in body weight and fat without affecting food intake

ER-alfa / ER-beta

  • In adipose tissue associated with
    • Obesity
    • Serum level and production of leptin in omental adipose tissue [2]
  • Localized in:
    • Nucleus
    • Plasma membrane
    • Mitochondria [2]

Estrogenní receptory alfa,beta-ERKO myši

  • žádný jasný nárůst váhy
  • Nezvýšený leptin [2]

Estrogenní receptor alfa

  • E2/ER alfa signaling is critical in female and male WAT and that obesity
    • Involves a mechanism of reduced energy expenditure [2]
  • E2 effects on adipose tissue are predominately through ER-alfa [2]
  • Ovariektomie in 8-week old female Wistar rats induced hyperphagia
    • Effects were fully reversed by subcutaneous E2 replacement [2]
  • Membrane pool of ER-alfa is likely not involved in E2 regulation of body weight and obesity [2]
  • Nuclear and mitochondrial pools of ER-alfa may be responsible for E2 regulation of body weight and obesity [2]
  • Detected in mitochondria of
    • HepG2
    • MCF-7 cells
    • Rat cerebral blood vessels [1]

Estrogen receptor alfa knocked out (alfa-ERKO) mice

  • Adipocyte hyperplasia/hypertrophy
  • Vzestup hmotnosti
  • Insulin resistance
  • Glucose intolerance [1]
  • Reduced energy expenditure in both sexes [2]
  • 10-fold increase in E2 [2]
  • Persistent / increased E2 signaling through ER-beta [2]
    • Obesity factor in alfa-ERKO mice ? [2]
  • Strong staining for ER-beta in adipose tissue [2]
  • Ovariectomized (Ovx) alfa-ERKO mice
    • Removing E2/ER-beta signaling in alfa-ERKO mice by ovariectomy
    • Poklesla hmotnost proti alfa-ERCO
      • 45% decreases in bodyweight and adipocyte circumference [2]
    • Nižší hladiny glukózy před i po gluk. inj. [2]s
    • Nižší hladiny inzulínu
    • E2 replacement (rušení účinků ovariektomie)
      • Zvýšila body weight na úroveň alfa-ERCO
        • O 16% tělesné hmotnosti [2]
      • Zvýšila hladiny glukózy před i po inj. glukózy i inzulínu [2]
      • Metabolické NÚ suplementace E2 menopauzálních žen s převahou ER-beta / mutacemi snižující funkci ER-alfa ???
      • Možnost využití anti-ER-beta v terapii lipedému ???
  • Expression of ER-alfa functional domain in plasma membrane in alfa-ERKO mice did not prevent from developing obesity [2]

Estrogen receptor beta signalizace

  • ER-beta mediated effects on adipose tissue are opposite of ER-alfa [2]
  • ER-beta inhibited ligand-mediated transcriptional activity induced PPAR-gamma [2]
    • Blockade of PPAR-gamma-induced adipocytic gene expression
      • Decreased adipogenesis
  • Involved in the anorectic action of estrogen [2]
  • ER-beta is present in mitochondria of
    • Uterus
    • Ovary
    • Rat primary neurons
    • Primary cardiomyocytes
    • Murine hippocampus cell lines
    • The perikarya and proximal dendrites of pyramidal
    • Granule cells of rat coronal hippocampus
    • Human breast cancer MCF-7
    • Liver cancer HepG2 cells
    • Heart cells[
    • Lens epithelial cells
    • Osteosarcoma SaOS-2
    • Sperm [1]

Estrogen receptor beta knock out (beta-ERKO) mice

  • Insulin resistance
  • Impaired glucose tolerance (Heine et al 2000) [1]
  • no difference in brown adipose tissue (BAT) weight mice of all ages
  • WAT increased with advancing age in male mice (Heine et al 2000) [1]
  • Reduced energy expenditure rather than increased energy intake (Heine et al 2000) [1]
  • Some mutations in human ER-beta gene
    • Obese adolescents and women with bulimic disease [2]
  • Inhibitory effects of E2 on food intake and bodyweight blocked
    • By anti-sense oligonucleotides of ER-beta in brain
      • Not blocked by antisense of ER-alfa [2]

Follicle-stimulating hormone receptor

  • Adult knock out mice gain bodyweight [1]

Aromatáza

  • Catalyzes the conversion of androgen to estrogen
  • Mice with knocked out aromatase (ARKO) became obese when fed the same amounts as normal mice [2]

Postmenopausal women

  • Have increased WAT
  • ERT restores WAT to lower levels (Tchernof et al 1998) [1]
  • estrogen therapy has positive effects on carbohydrate and lipid metabolism in overweight-obese younger postmenopausal women [2]

Tamoxifen (TAM)

  • Anti-estrogen
  • Attenuated the effects of E2 on reducing body weight [2]

ICI 182,780

  • Pure estrogen antagonist of E2
    • On estrous behavior
    • Energy balance in Syrian hamsters [2]

Literatura:

[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.
[2] Regulation of Energy Metabolism Pathways by Estrogens and Estrogenic Chemicals and Potential Implications in Obesity Associated with Increased Exposure to Endocrine Disruptors. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2747085/?tool=pmcentrez >.

Hypometylace - Epigenetický imprinting

  • Myši obézní matkou dávaná epigentická dispozice k obezitě
    • Lze vyrušit methyl donor supplementation
      • Role of DNA methylation in transgenerational amplification of obesity ? (Waterland et al, 2008)[1]

Hypothyroidism


Hypoxie tukové tkáně

  • Solubility of oxygen in fat and oil
    • Five times higher than in water [8]
  • Dissolved oxygen in fat
    • Around 5 mg/100 mL
  • Dissolved oxygen in water
    • About 0.9 mg/100 mL [8]
  • Saturation and desaturation of adipose tissue with oxygen
    • Is comparable to that of nerve and brain tissue
    • Takes more time than that of, for example, muscle tissue
      • For bone, cartilage and tendon tissue, this process takes even longer [8]
  • Difficult to estimate
    • When the effect of transient hypoxia reaches fat tissue
    • How fast reoxygenation can lead to oxidative stress [8]
  • PO2 of white adipose tissue
    • Completely saturated with oxygen in a healthy lean young adult
      • 55–60 mmHg - not far from arterial blood pO2 [8]

  • PO2 in interstitium of white adipose tissuein in lean individuals
    • 60 mmHg [8]
  • PO2 in obese individuals
    • 80 mmHg
      • Impaired adipocytes with higher inflammatory markers
        • Insulin resistance
        • Lower oxygen consumption [8]
      • Reduced arterial blood flow of obese individuals

  • Intermittent hypoxia may have accumulative effects
  • After some hours of hypoxia, adipocytes start to adapt to the hypoxic stimulus accompanied by oxidative stress reduction
  • Older adipocytes seem to be somewhat more “relaxed” in their reaction to hypoxia [8]
  • Impaired insulin action in adipocytes associated with
    • Elevated lipolysis
    • Increased release of free fatty acids
      • Leading to ectopic fat deposition
        • Liver
        • Skeletal muscle [8]
  • Chronic hypoxia
    • Derangements in lipid metabolism
      • Reduced lipoprotein clearance
        • By decreasing lipoprotein lipase activity [8]
    • Diminished subcutaneous adipose tissue lipolysis
      • Decreased efficiency of beta-adrenergic, growth hormone and parathyroid hormone lipolytic signaling in humans
  • Acute hypoxia
    • Increase lipolysis
      • Increased epinephrine and norepinephrine by activated sympathetic nervous system
        • Activation of adipose protein kinase A [8]
  • Propranolol treatment
    • Markedly reduced lipolysis in this experiment [8]

  • Hypoxia increased in human adipocytes
    • GLUT-1, GLUT-3 and GLUT-5 gene expression
    • GLUT-1 protein in response to hypoxia
    • Glucose uptake [8]
  • Ob/ob mice, adipose tissue hypoxia
    • Free fatty acid release
    • Inhibited glucose uptake in adipocytes
      • Inhibition of the insulin-signaling pathway [8]
  • Different metabolic effects
    • In non-obese and obese individuals
    • Types of adipose tissue [8]

  • All metabolic processes in adipose tissue depend on blood supply
  • Blood flow is mainly regulated:
    • Fasting conditions
      • Vasodilatory
      • Vasoconstrictive
        • Alpha 2-adrenergic
        • Angiotensin II [8]
    • Postprandially
      • ß-adrenergic stimulation becomes important [8]
  • Disturbances in the regulation of adipose tissue blood flow
    • Linked to obesity and insulin-resistance [8]
  • Fasting adipose tissue blood flow
    • Reduced in obese [8]
  • Adipose tissue blood flow
    • Predominantly regulated by glucose and insulin [8]
  • Diminished blood flow
    • Associated with dyslipidemia in the fasting and postprandial periods [8]
  • Abdominal adipose tissue is associated with
    • Unfavorable changes in adipose tissue blood flow
    • Development of metabolic disorders [8]
  • Exposed to moderate systemic hypoxia
    • Subcutaneous adipose during exercise in hypoxia [8]
  • Hypoxia may occur within adipose tissue
    • Due to the obesity-associated expansion of adipocytes
    • Reduction in capillary density
    • Reduction of blood flow [8]
  • Extremely low or high levels of pO2
    • Lead to oxidative stress
      • Increase macrophage infiltration [8]
    • Pro-inflammatory response in adipocytes
      • Induces expression of genes related to activation of NF-?B and HIF-1?:
        • TNF-?, IL-1, IL-6,
        • Monocyte chemoattractant protein-1 [8]
        • Plasminogen activator inhibitor-1
        • Macrophage migration inhibition factor
        • Inducible nitric oxide synthase
        • Matrix metalloproteinases 9, and MMP2 [8]
  • Increased ROS secretion into peripheral blood from adipose tissue involved in
    • Induction of insulin resistance in skeletal muscle and adipose tissue
    • Impaired insulin secretion
    • Atherosclerosis
    • Hypertension [8]
  • Transient increase of ROS
    • Important for the insulin signaling pathway
    • Might prevent further lipid storage
      • Suppressing lipogenic genes [8]
  • In vivo pO2 levels (3%–11% O2)
    • Conflicting results were found [8]
  • Concentrations of 10% O2 and below increased
    • Adipocyte triacylglycerol content
    • Secretion rates of IL-6
    • Dipeptidyl-peptidase-4 [8]
  • Mice that were exposed to chronic hypoxia for 21 days (8% O2) showed
    • Decreased adipocyte size
    • Improved mitochondrial function
    • Decreased macrophage infiltration [8]
  • In obese men, ten nights of hypoxic exposure (15% O2)
    • Increased whole-body insulin sensitivity [8]
  • Obstructive sleep apnea syndrome - cycles of severe hypoxia)
    • Risk factor for insulin resistance [8]
  • Dose, duration, and patterns of hypoxic exposure may determine the effects on metabolic and cardiovascular health [8]
    • Zda např. vzniká acidóza (obstrukce, hromadění CO2) nebo alkalóza (usilovnější dýchání, pokles CO2)

  • Vasculature cannot expand with adipocyte hypertrophy
    • Hypoxia
    • mitochondrial dysfunction
    • Oxidative stress are consequences [8]
    • Impaired adipokine secretion
    • Inflammation [8]

Citrate-malate cycle

  • Oxidation-reduction balance
  • Simultaneous transfer of the acetyl group
    • From its site of formation
    • To its site of utilization [3]

Adenosine triphosphate [ATP]-citrate lyase = ATP-citrate lyase = ACL

  • Citrate exits the mitochondria to be converted by ATP-citrate lyase to acetyl-CoA for lipid synthesis
  • ACL is required for malonyl-CoA formation
  • Mammalian lipogenesis and cholesterogenesis
  • Linking cellular glucose catabolism and lipogenesis
  • Converting cytosolic citrate to acetyl-coenzyme A (CoA) [6]

Aktivace

  • Regulated in vitro allosterically by phosphorylated sugars as well as covalently by phosphorylation

Hepatic ACL deficiency

  • Significantly down-regulated expression of gluconeogenic genes in the liver
  • Enhanced insulin sensitivity in the muscle
  • Improved systemic glucose metabolism [6]

Inhibice ACL

  • Suppressing ACL expression
    • Proposed to prevent tumor growth [7]
    • Via small interfering RNA
    • Decreased global histone acetylation
      • In several different mammalian cell types
      • Histone acetylation depended on glucose
        • Fatty acids unable to substitute
        • Requirement for a cytosolic or nuclear (not mitochondrial) pool of acetyl-CoA [7]
  • L-glutamate
    • In vitro in differentiating adipocytes
      • Prevented the expression
        • Glut4
        • Hexokinase 2 (HK2)
        • Phosphofructokinase-1 (PFK-1)
        • Lactate dehydrogenase–A (LDH-A)
      • Rescued by treating cells with acetate
  • Potentially novel class of hypolipidemic agents
    • Citric acid analogues 5-16
      • Irreversible inhibitors of the enzyme
        • Active-site nucleophile (thiol)
      • Reversible inhibition
        • Compounds 5, 10, and 12-16 [7]
  • ShRNA-ACL - small hairpin RNA (shRNA)
    • Inhibition of ACL expression
    • Decreased glucose incorporation into palmitate
    • Increased fatty acid oxidation in INS 832/13 cells [8]

Fatty acid synthase (FAS)


Acetyl-coenzyme A carboxylase


Hypoxie - isocitrate dehydrogenase-1 (IDH1)-dependent pathway

  • A reductive metabolism of alpha-ketoglutarate
    • Carboxylation of glutamine-derived ?-ketoglutarate
  • Synthesize AcCoA for de-novo lipid synthesis
  • Active in most cell lines under normal culture conditions
  • Cells grown under hypoxia almost exclusively
  • Renal cell lines deficient in the von Hippel–Lindau tumour suppressor protein
    • Preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels [5]

ICI 182,780

  • Pure estrogen antagonist of E2
    • On estrous behavior
    • Energy balance in Syrian hamsters [2]

IL-10 Expression

  • Lower levels of IL-10
    • Symptoms of metabolic syndrome, whether obese or nonobese
    • Possibly due to the distribution of M1/M2 macrophages
  • IL-10 in nonobese but overweight female adolescents
    • Correlated with levels of TNF alpha and IL-6
  • In more healthy but still overweight phenotypes, IL-10 is upregulated to suppress inflammation [16]

Obezita jako infekce

  • In fact, prevalence of obesity in friends and family clusters was recently reported (Christakis et al 2007)[1]
    • Longitudinal study showed increased chances to “contract” obesity, if a spouse, sibling or friend became obese. [1]
    • This spread of obesity appeared to spread through social ties. [1]

Infekce a imunitní systém a obezita

  • Adipocytes and macrophages have many similar functional characteristics [1]
  • Preadipocytes have the ability to differentiate into macrophages (Charriere et al 2003) [1]
  • Adipose tissue might expand in response to certain infections [1]

Macrophage colony stimulating factor (MCSF)

  • Proinflammatory marker increased in obesity
  • Overexpression of MCSF in adipose tissue (Levine et al 1998) [1]
  • Might be that obesity promoting pathogens stimulate MCSF production leading to the growth of adipose tissue ? [1]
  • Is the inflammation a cause or effect of obesity ? [1]

Infekčnost obezity

  • In fact, prevalence of obesity in friends and family clusters was recently reported (Christakis et al 2007)[1]
    • Longitudinal study showed increased chances to “contract” obesity, if a spouse, sibling or friend became obese. [1]
    • This spread of obesity appeared to spread through social ties. [1]

Adenovirus ptačí

Adenoviry lidské

Ad-5

Myši

  • Adenovirus type 5 (Ad-5) induced adiposity in mice (So et al 2005) [1]

Ad-9

  • Enhance 3T3-L1 differentiation
  • Reduce leptin secretion in vitro (Vangipuram et al 2007)[1]

Ad-31

  • Increase 3T3-L1 differentiation in vitro (Whigham et al 2006) [1]

Kuřata

  • Increased adiposity in chickens [1]

Ad-36

  • Increases adiposity in experimentally infected chickens, rats, mice and marmosets (non-human primates) (Dhurandhar et al 2000; 2001; 2002; Pasarica et al 2006)[1]
  • Without inducing detectable hyperphagia
  • Reduces serum cholesterol and triglycerides (Dhurandhar et al; 2000,Dhurandhar et al; 2001; 2002,) [1]

Kosmani - Marmosets

  • Infekcí 4x gain in body weight [1]
  • Increase in total body fat (36±6 g vs 23±3 g) [1]

Potkani

  • Central and peripheral effects (Pasarica et al 2006)
  • Decreased norepinephrine levels in the paraventricular nucleus, arcuate nucleus, dorso-medial hypothalamus and ventro-medial hypothalamus
  • Dopamine and 5-hydroxyindolacetic acid also reduced in some of these brain regions
  • Increased whole body insulin sensitivity
  • Enhanced expression of genes involved in the adipogenic and de-novo lipogenesis pathway:
    • Fatty acid synthase (FAS) [1]
    • Acetyl-CoA carboxylase (ACC-1) (Vangipuram et al 2007) [1]
  • 4 dny po infekci Ad36 spreads to adipose tissue, liver, kidney, and brain
  • Lowers inflammatory cytokine levels
  • Infected rats have increased epididymal fat pad weight (Pasarica et al 2008b) [1]
  • Ad36 could be used as a tissue engineering tool for building adipose tissue [1]

In vitro lidské buňky

  • Differentiation and lipid accumulation of 3T3-L1 and human primary preadipocytes (Vangiparum et al 2004; Rathod et al 2009)[1]
  • Viral mRNA expression required for this adipogenic effect (Rathod et al 2007) [1]
  • Activates phosphotidyl inositol kinase (PI3K)
  • Aktivuje cAMP pathways [1]
  • Increases cell replication [1]
  • Zvyšuje expressi PPAR?, CEBP/ß [1]
  • Induces differentiation and lipid accumulation in 3T3-L1 cells and human adipose derived stem cells (hASC) (Rogers et al 2007; Rathod et al 2009) [1]
  • Robustly induces adipogenic commitment, differentiation and lipid accumulation (Pasarica et al 2008a).[1]
  • E4 orf-1
    • Viral gene
    • Required and sufficient for this adipogenic effect of Ad-36 (Rogers et al, 2007) [1]

In vitro hlodavčí buňky

  • Ad-36 reduces leptin expression and secretion in rodent fat cells
  • Increases glucose uptake by increase of PI3K activation in:
    • Primary rodent adipocytes (Vangipuram 2007)
    • Human adipose tissue explants or hASC (Rogers et al 2007, Vangipuram et al 2007)
    • Human primary skeletal muscle cells (Wang et al 2008) [1]
  • In Ad-36 infected adipocyte progenitors
    • Increased glucose uptake
    • De-novo lipogenesis
    • Greater replication, differentiation
    • Lipid accumulation [1]

Lidé

  • Natural infection associated with human obesity
  • 17% of the 500+ subjects screened, showed seropositivity to Ad-36 (Atkinson et al 2005) [1]
    • 30% percent of the obese
    • 11% of the non-obese subjects
  • Obese and non-obese seropositive groups
    • Significantly heavier than seronegative counterparts
  • Ad-2 or Ad-31 non-adipogenic adenoviruses (Whigham et al 2006) showed equal distribution among the obese and non-obese groups
    • no association with BMI
      • = Ad-36 seropositivity neznamenala increased propensity to catch infection
      • = Ad36 causatively contributed to their obesity
  • Seropositivity associated with lower levels of serum cholesterol and triglycerides (Dhurandhar et al 2000; 2001; 2002)[1]
  • In twins discordant for antibody status
    • Seropostive twins were heavier and fatter compared to their seronegative counterparts (Atkinson et al 2005) [1]

Ad-37

  • Animals developed increased adiposity (Dhurandhar et al 1990; 1992; 2000; 2001; 2002; Whigham et al 2006; So et al 2005) compared to controls despite similar food intake [1]
  • Enhance 3T3-L1 differentiation
  • Reduce leptin secretion in vitro (Vangipuram et al 2007)[1]


Borna Disease virus

Potkani

  • Cause obesity in rats (Gosztonyi et al 1995) [1]
  • Damaging the hypothalamus [1]
  • Neuroendocrine dysregulations (Herden et al 2000) [1]

Canine distemper virus (CDV)

  • Obesity promoting virus (Lyons et al 1982) [1]

Myši

  • Obesity develops after acute infection of mice when no virus is detectable [1]
    • “hit and run” (Bernard et al 1999; Nevels et al 2001) [1]
  • Decreases levels of melanin concentrating hormone (Veraeten et al 2001) [1]
  • Down-regulates leptin receptors in the hypothalamus (Bernard et al 1999) [1]

Chlamydophila pneumoniae

  • Association with higher BMI in humans (Ekesbo et al 2000; Dart et al 2002) [1]
    • Others found no association (Blanc et al 2004; Falk et al 2002; Muller et al 2003) [1]
  • Antibody positive subjects
    • Older
    • Lower socioeconomic status
    • Higher fasting insulin levels [1]
  • Is obesity is associated with impaired immune function ? (Marti et al 2001) [1]

Eugregarinorida (Apicomplexa)

  • Non-invasive gregarine gut parasite

Dragonflies (Libellula pulchella)

  • Symptoms similar to human metabolic syndrome (Schilder et al 2007) [1]
    • Higher thoracic lipid accumulation [1]
    • Inability to oxidize fatty acids in muscle tissue [1]
    • Higher hemolyph carbohydrate concentrations [1]
    • Increased insulin resistance
    • Elevated markers of a chronic inflammatory state [1]
  • Factors secreted by the parasites were considered responsible for the phenomenon
    • Exact mechanism is unknown [1]

Lipopolysaccharide (LPS)

  • Proinflammatory bacterial cell wall component
  • By the death of gram negative bacteria and absorbed into the body
  • Sepeticemia
    • Plasma LPS rise 10 to 50 fold
    • Induce anorexia
    • Other metabolic effects
  • Less dramatic LPS increase
    • Induce weight gain and metabolic changes ::1

Myši

  • Na high fat diet
    • Increased plasma LPS cca 2 x
    • Reduced gram-negative bacteriodetes in their gut
    • Increased body weight and insulin resistance (Cani et al 2007)
  • Infusion of exogeneous LPS to mimic its plasma levels
    • Similar to a high fat diet
    • Weight gain
    • Impaired glycemic response

Rous-associated virus-7 (RAV-7)

  • Avian retrovirus

Kuřata

  • Stunted growth, obesity and hyperlipidemia in chickens (Carter et al 1983a & b) [1]
  • Decreased thyroid hormone levels (Duff et al 1969) [1]

SMAM-1

Kuřata

  • 53% increase in visceral fat in three weeks after inoculation (Dhurandhar et al 1990; 1992) [1]
  • Horizontal transmission - visceral adiposity [1]
  • Reduction in serum cholesterol and triglycerides [1]
    • Tuková tkáň získala větší kapacitu = oddálení projevů metabolického syndromu

Svědivka / svrbivka - scrapie agents

Myši

  • Induces obesity in mice (Kim et al 1987; Carp et al 1998) [1]
  • Disrupt normal glucose metabolism
  • Hyperglycemia resulting in disrupted transvascular glucose transport in some regions of the brain (Vorbrodt et al 2001)
  • May lead to functional dysregulation of hypothalamus and consequential adiposity [1]

Inhibitors of MEK (mitogen-activated protein kinase pathway)

  • Block catecholamine
    • Block beta(3)-stimulated lipolysis by approximately 30%


INS - třídy alel kódující inzulín

  • Variable number of tandem repeats (VNTR) at the locus [1]

Class I VNTR allele

  • Predispose to childhood obesity
  • Only when inherited from the father (Le Stunff et al., 2001) [1]
  • When inherited from the mother, the allele is epigenetically silenced
    • Protection from the obesigenic effects of the class I VNTR polymorphism [1]

Insulin resistance


Insulin

  • Increases in phosphodiesterase-3B (PDE-3B) activity
    • Snižuje intracellular cAMP [7]
  • Changes cAMP to AMP via the activation of protein kinase B/AKT [7]
  • Inhibitory effect of insulin
    • On HSL activity
      • Increase in its phosphorylation at Ser565
    • AMP activated protein kinase (AMPK)
  • Marked increase in oxygen consumption during lipogenesis stimulated by insulin in adipose tissue [3]
  • Stimulates fatty acid synthesis in white and brown fat cells as well as in liver and mammary tissue [4]
  • Stimulating pyruvate dehydrogenase phosphatase [4]
    • Fosforylace Acetyl-CoA carboxylase within fat cells on a specific site on the enzyme [4]
  • Mitotic factor for white adipocytes [80]


Inzulinorezistence matky

  • Více tukové tkáně u dítěte
  • Dvakrát vyšší riziko rozvoje obezity mají novorozenci od porodní hmotnosti nad 4000 g (Schellong et al., 2012) [5]
  • Navýšení růstového tempa novorozence/batolete o jednu směrodatnou odchylku zvyšuje dvojnásobně riziko nadváhy (Ong et al., 2000) [5]

IUGR

  • Uterine environment with reduced placental blood flow
    • Reduced nutrient transport
    • “thrifty phenotype”
    • Lifetime of undernourishment [68]
  • Intrauterine growth restricted (IUGR) rats
    • Subsequently exposed to a highly palatable diet (to mimic the modern fast food diet with excessive calories)
    • Unable to regulate their body weight
    • Resulting in weight gain
    • Higher risk for subsequent obesity, type 2 diabetes and hypertension [68]
  • Best predictor of insulin resistance in 8-year-old children
    • Combination of being light at birth
    • Associated with a high postnatal growth velocity
      • “centile crossing”
    • Critical factor in the eventual health status of a person [64]

Nechutenství

Medikamentózní terapie povzbuzující chuť k jídlu

Kortikosteroidy

Prednison

  • 15mg denně

Dexametazon

  • 3-6 mg denně
  • Zlepšují proti placebu významně chuť k jídlu
  • účinek je krátkodobý

Gestageny

Megestrol acetát (Megace)

  • účinným způsobem zvyšuje chuť k jídlu u nemocných s nádorovu kachexií a anorexií
  • Efekt přetrvává po dobu léčby
  • U podstatné části nemocných dochází i k vzestupu tělesné hmotnosti
  • Hlavním NÚ
    • Otoky - přítomnost již před zahájením léčby může být relativní kontraindikací léčby
    • Riziko hluboké žilní trombózy (u maligních onemocnění již tak zvýšené)

Medroxyprogesteron acetát (Provera)

  • Gestagenní hormon, který má podobné účinky jako Megace

Kannabinoidy

Dronabinol

­u onkologicky nemocných signifikantně stimuluje chuť k jídlu
  • Lze očekávat i antiemetický účinek, nikoliv však vzestup tělesné hmotnosti

Nesteroidní antiflogistika

Ibuprofen

  • Ale i některé další NAF
  • Snižují hladiny bílkovin akutní fáze, IL-6 a kortizolu
  • Do určité míry upravují kinetiku bílkovin u kachetizujících nemocných s kolorektálním nádorem
  • Snižují také klidový energetický výdej
  • Mohou stabilizovat tělesnou hmotnost a kvalitu života u nemocných s nádorem slinivky břišní

Kyselina eikosapentaenová (EPA)

  • Esenciální polysaturovaná mastná kyselina n-3 řady z rybího oleje
  • V dávkách 2-6 mg denně
  • Snižuje produkci prozánětlivých cytosinů
  • Redukuje hladiny bílkovin akutní fáze
  • Má protizánětlivé účinky
  • Snižuje mobilizaci endogenních lipidů
  • Může vést ke stabilizaci tělesné hmotnosti u nemocných s nádorovou kachexií
  • Může dokonce zpomalovat růst některých nádorů

Antidepresiva

Mirtazapin


Další doporučení (u onkol. nemocných)

  • léčba příznaků choroby, které mohou významně snižovat příjem stravy:
    • Bolest
    • Dušnost
    • Zácpa
    • Nevolnost
    • Zvracení a pod.
  • Zrušit dietní omezení, která nejsou zcela nezbytná
    • Vyvarujte se tučných, mastných, smažených jídel a jídel velmi sladkých či kořeněných
    • Nepodávat pacientova oblíbená jídla v době:
      • Léčby cytostatiky
      • Ozařování
      • Zhoršení nevolnosti, aby nedošlo ke vzniku averze k těmto jídlům
    • Nejezte nejméně 2 hodiny před podáním chemoterapie a před ozařováním,
  • Jíst v části dne, kdy se nemocný cítí nejlépe
    • Může jíst, kdykoliv pocítí chuť
    • Jíst po malých porcích 6 – 8x denně
  • Intenzivní péče o dutinu ústní, každodenní
  • kloktat nebo vytírat dutinu ústní borglycerinem několikrát denně, před každým jídlem [2]
  • Omezit příliš intenzivní pachy jídla při jeho přípravě i servírování,
  • chlazené potraviny a nápoje mohou být lépe přijímány
  • Zkuste nápoj zmrazit a cucat ledové kostky
  • Jezte pomalu, jídlo dobře rozžvýkejte
  • Jezte v dobře větrané místnosti, ne v příliš teplém prostředí
  • Po jídle odpočívejte
  • Noste volný oděv
  • Po epizodě zvracení zkuste po lžičkách malé množství čirých tekutin, zpočátku každých 20 – 30 minut a postupně množství zvyšujte

Literatura:

[1] MIČOVÁ, Lenka . Diabetik s nádorovým onemocněním [online]. Brno : ?, 2009. ? s. Diplomová práce. Ústav preventivního lékařství LF MU. Dostupné z WWW: < is.muni.cz/th/20015/lf_b/Bc_prace_MicovaDM_Onko.txt?lang=en >.
[2] Bc. Petr Slováček, Nutriční poradenství v onkologii (kasuistiky 20 pacientů[online]. MASARYKOVA UNIVERZITA V BRNĚ, LÉKAŘSKÁ FAKULTA , Ústav preventivního lékařství, DIPLOMOVÁ PRÁCE, VÝŽIVA ČLOVĚKA, Brno, květen 2006, Dostupné z WWW: < is.muni.cz/th/60176/lf_m/Diplomova_prace1.doc >.

Káva

Mechanismy, kterými pravděpodobně přispívá pití kávy ke vzniku obezity

  • Jedná se o moje vlastní úvahy a doměnky
  • Dále vycházím z vlastní zkušenosti se závislostí na kávě a opakovanými fázemi abstinence
  • Něco lze přímo dohledat v různých studiích, ale spoustu si toho pouze domýšlím na základě znalosti různých souvislostí
    • Slabý vliv je těžké prokázat mezi stovkami jiných silnějších vlivů

Suprese syntézy melatoninu, pokud se pije večer

  • Přímá inhibice syntézy melatoninu
    • Méně melatoninu = prozánětlivý vliv, stresor, vliv zvyšující hladiny inzulínu, ovlivnění poměrů T4, T3, rT3 - snížené spalování enenrgie
      • Nevyspalí lidé - nechtějí se hýbat, ospalost zahání další kávou a sladkostmi, jsou zimomřiví
        • Kumulace faktorů vedoucích k rozvoji obezity

Nižší hladiny melatoninu při dlouhodobě větší konzumaci kávy

    • Timulace jaterních detox. enzymů, které pak zvýšeně odbourávají i melatonin
    • Při současném užití tablety melatoninu a kávy/čaje/kofienu ap. je odbourávání melatoninu kompetitivně zpomaleno

Browning products - prvky spálenin

  • Prozánětlivé a prokancerogenní látky, které v těle vyvolávají prozánětlivý stav
    • Vede ke stimulaci tukové tkáně
    • Vede k inzulínové rezistenci
      • Cokoliv vede k inzulinové rezistenci, způsobuje vyšší hladiny inzuilínu v krvi a vznik obezity

Zvyšují vjěmy bolesti

  • Bezprostředně po vypití bolest mírně potlačuje vč. duševního diskomfortu
    • Z dlouhodobého hlediska však zvyšuje odbourávání vápníku z kostí - potencováno nedostatkem vitamínu D (nosnost dutých hlavic - to, co je pod chrupavkami velkých kloubů - když se to pod nimi vahou človkěa zboří, nejsou již dál hladké)
  • Zesiluje prozánětlivý stav v těle
    • A při vyšší konzumaci kávy denně nad 3 šálky opravdu znatelně roste míra, frekvence a počet různých kloubních bolístek
      • Podporuje rozvoj zánětlivých a degenerativních změn kloubů
  • člověk s bolestí kloubů má ještě méně chuť se hýbat než před tím
    • Další faktor k rozvoji obezity

Zvyšují jaterní odbourávání estrogenů

  • Další rizikový faktor přispívající k obezitě, hlavně u žen

Zvyšuje střevní propustnost

  • Další prozáněltivé působící vliv, který je možno asociovat i s obezitou
    • Průnik dalších prozánětlivých molekul - inzulínová rezistence, kumulace tuku centrálně i jaterní steatoza

Katechiny

  • Možná i ty kávové podobně jako ty čajové mohou potlačovat funkci/vznik T3 a T4 ze štítné žlázy

Pokud se pije s mlékem

  • Silný simul pro vyplavení inzulínu
    • Každé vyšší vyplavení inzulínu navíc blokuje lipolýzu, stimuluje ukládání tuku

Slazení či sladidla

  • Vyvolávají chutě a hlady s odstupem času na další kávu nebo další jídlo

Zubní kámen

  • Při neprovedené očistě zubů před pitím kávy - vzniká na zubech zubní kámen
    • Další základ pro přemnožení patogenních bakterií v ústech a prozánětlivý vliv
      • Nárůst bakteriální vegetace a toxinů, které v dutině´ústní vznikají a vstřebávají se

Snížený pocit žízně

  • Stačí dát si jedinou kávu a sama na sobě zaznamenám výrazný pokles chuťe pít vodu
  • I když je močopudná, pití spíše potlačuje
    • Horší vyplavování browning prouducts z těla popř. ketolátek aj.
      • Jejich silnější prozánětlivé působení, vyšší kumulace tuku

Zvýšené ztráty AMK do moči

  • Aby mastné kyseliny byly efektivně spalovány v játrech - potřebují tam být odtransportovány na albuminu/jiných bílkovinách
  • Nadměrné pití kávy při nedostatečné stravě na bnílkoviny by toto mohlo ev. ještě dále zhoršit

Zákusky

  • Spousta lidí ke kávě potřebuje něco mlsat a mají na to návyk

Léky, které snižují energetický výdej

Léky stimulující diferenciaci adipocytů

  • Thiazolidindiony

Léky aktivující lipogenezi

  • Inzulin
  • Deriváty sulfonylurey

Stimulují chuť k jídlu

Leptin -LEP mutations

  • Monogenic obesity in humans (Rankinen et al., 2006) [1]
  • Promoters of LEP gene contain regions with a high density of CpG sites [1]
  • Cytosine methylation at such CpG islands functions to silence genomically imprinted alleles and genes on the inactive X chromosome [1]
  • Most promoter region CpG islands are unmethylated in normal tissues (Shen et al., 2007) [1]
  • LEP and POMC CpG islands exhibit tissue-specific methylation
    • Correlates with expression [1]
  • The LEP CpG island slightly hypomethylated in human adipose tissue DNA relative to peripheral blood DNA (Stoger, 2006)
    • Consistent with the adipocyte-specific expression of leptin [1]
  • More striking tissue-specific hypomethylation
    • Might be in isolated primary adipocytes
      • Most DNA in adipose tissue is derived from non-leptin-expressing stromal-vascular cells
      • Human pre-adipocytes (which do not express leptin) CpG islands are hypermethylated [1]
      • Leptin expression of differentiated adipocytes
        • Correlated with LEP CpG island hypomethylation (Melzner et al., 2002) [1]
  • “obesity genes” are regulated by epigenetic mechanisms [1]

Lipogenic genes

  • FAS
  • SCD1,
  • SREBP-1c

Lipopolysaccharide (LPS)

  • Proinflammatory bacterial cell wall component
  • By the death of gram negative bacteria and absorbed into the body
  • Sepeticemia
    • Plasma LPS rise 10 to 50 fold
    • Induce anorexia
    • Other metabolic effects
  • Less dramatic LPS increase
    • Induce weight gain and metabolic changes ::1

Myši

  • Na high fat diet
    • Increased plasma LPS cca 2 x
    • Reduced gram-negative bacteriodetes in their gut
    • Increased body weight and insulin resistance (Cani et al 2007)
  • Infusion of exogeneous LPS to mimic its plasma levels
    • Similar to a high fat diet
    • Weight gain
    • Impaired glycemic response

Proteins secreted by macrophages

  • Mitogens in human preadipocytes (Lacasa et al., 2007) [80]

Makrofágy a infekce

  • Adipocytes and macrophages have many similar functional characteristics [1]
  • Preadipocytes have the ability to differentiate into macrophages (Charriere et al 2003) [1]
  • Adipose tissue might expand in response to certain infections [1]

Macrophage colony stimulating factor (MCSF)

  • Proinflammatory marker increased in obesity
  • Overexpression of MCSF in adipose tissue (Levine et al 1998) [1]
  • Might be that obesity promoting pathogens stimulate MCSF production leading to the growth of adipose tissue ? [1]
  • Is the inflammation a cause or effect of obesity ? [1]

Accumulation of macrophages and monocytes in the tissue

  • Alter the nature of the tissue
  • Extensive tissue remodeling
  • Adipose tissue into an endocrine organ
  • Can mediate further levels of inflammation
  • Excess
    • fat storage
    • Release numerous pro-inflammatory cytokines and chemokines [38]

M1 Pro-inflammatory macrophages (M1)

  • Predominate over anti-inflammatory macrophages (M2) in obese [38]

M2 macrophages

  • Alternatively activated by
    • IL-4 stimulation
    • Peroxisome proliferator-activated receptor gamma receptor
  • Protect against the metabolic consequences of obesity in mice
  • PPAR gamma upregulation
    • Coincides with increased expression of IL-10
      • An anti-inflammatory cytokine and M2 marker

Malic enzyme 1 -ME

  • Key lipogenic enzyme [70]
  • Important during differentiation
  • S14, a T3-target gene [80]
  • Present in many lipogenic tissues
  • Genes increase during differentiation of adipocytes [80]

Adipogeneze markery

  • Preadipose cells lines derived from NIH 3T3 fibroblasts (3T3-L1 and 3T3-F442) - množení a diferenciace
    • Lipogenic and glycolytic enzymes
      • The glycerophosphate dehydrogenase (GPD)
      • The lactic dehydrogenase (LDH)
      • The acetyl-CoA carboxylase (ACC)
      • The fatty-acid binding protein aP2
      • The stearoyl-CoA desaturase (SCD)
      • The fatty acid synthase (FAS)
      • The lipoprotein lipase (LPL)
      • Malic enzyme (ME)
      • Phosphoenolpyruvate carboxykinase (PEPCK)
      • Adipsin
      • AdipoQ - adiponectin [80]
    • Transcription factors C/EBPs
      • One of the earlier molecules necessary for the adipocyte phenotype [80]

Markery proliferace adipocytů

  • Several HOX genes
    • Identified as transcription factors that trigger the transition
  • Several HOX genes
    • Specific expression in WAT [80]
  • 4 HOX genes (HOXA4, HOXB4, HOXC4, HOXD4)
    • Discriminate between WAT and BAT [80]
  • Leukemia inhibitory factor (LIF) [80]
  • C/EBP and Necdin
    • Expressed during the proliferation of brown as well as white preadipocytes [80]
  • Necdin
    • Imprinted gene
    • Expressed in the paternal allele
    • Inhibits the activation of PPAR gamma 1 promoter [80]

Mateřská péče

  • Changes in offspring DNA methylation based on differences in maternal caregiving behavior [1]

Medikace a hmotnost

Antipsychotika

Olanzapine

  • Olanzapine to ziprasidone
    • Lost weight when switched to ziprasidone
    • Improvements in lipid profile and glucose tolerance [1]

Chlomipramine

  • Weight gain and increased food intake in humans
  • Decreases food intake in animals (Calegari et al., 2007) [1]

Clozapine

  • Hyperphagia and weight gain in humans [1]
  • Increase in triglyceride
  • 37% increase in the incidence of type 2 diabetes over the 5-year period of observation (Henderson et al., 2000) [1]

Thioridazine/mesoridazine

Ziprasidone

  • Mnohem menší nárůst váhy než Clonazapin [1]

Risperidone

  • Produced less weight gain than did sertindole, olanzapine, or clozapine [1]

Sertindole

Tricyklická antidepresiva

  • Amitryptyline - jeden z nejobezitogennějších TAD
  • Nortriptyline (Weber et al., 2000)
  • Doxepin (Feighner et al., 1986) [1]

Selective serotonin reuptake inhibitors (SSRIs)

  • Paroxetine appears to be more likely to cause weight gain than other agents (Sussman et al., 2001) [1]
  • Weight gain in humans
  • Weight loss and reduced food intake in animals (Konkle et al., 2003) [1]
  • SSRIs
    • Associated with greater initial weight loss than nefazodone during acute treatment (Sussman et al., 2001) [1]
    • Long-term treatment SSRI-treated patients gained weight compared to nefazodone-treated [1]
    • Imipramine produced greater weight gain than did nefazodone during both the acute treatment phase and long-term treatment [1]

Monammine oxidase inhibitors

Atypical antidepressants

  • Buproprion
    • May be associated with weight loss (Croft et al., 2002) [1]
  • Nefazodone
    • Reportedly weight neutral (Sussman et al., 2001)
    • Appear to cause less weight gain in the long term [1]

Lithium

  • Přibírání váhy occurring in one third to two thirds of patients (Garland et al., 1988; Baptista et al., 1995) [1]

Antidiabetics

  • Sulfonylureas
  • Thiazolidinediones
  • Insulin
  • metformin
    • Pokles hmotnosti

Antihypertensives

  • ß-adrenergic blockers

Steroid hormones

  • Prednisone

Contraceptives

Antihistamines

Protease inhibitors

  • Antiretroviral therapy and protease inhibitors anti HIV regimens

Další rizika obezitogenní medikace

  • Type II diabetes
  • Hypertension
  • Hyperlipidemia
  • Poor medication compliance [1]
Literatura:

[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.

Medikace a nárůst hmotnosti

  • Stimulují chuť k jídlu
  • Aktivují lipogenezi
    • Inzulin
    • Deriváty sulfonylurey
  • Stimulují diferenciaci adipocytů
    • Thiazolidindiony

Antipsychotika


S

MEK inhibitors

  • Decrease dioctanoylglycerol-stimulated activation of lipolysis
  • Two different inhibitors of MEK (upstream activator of ERK)
    • Block catecholamine
    • Block beta(3)-stimulated lipolysis
      • By cca 30% [77]

Melanin-concentrating hormone


Metylace - Různost genové exprese

  • During prenatal and early postnatal development and function throughout life
  • Diverse gene expression

Methylation of cytosines

  • Within CpG dinucleotides

Modifications of the histone proteins

  • Package DNA in the nucleus

Cell-autonomous expression of myriad autoregulatory DNA binding proteins


Methyl supplementation

Myši

  • Female mice before and during pregnancy
  • Induces DNA hypermethylation at “metastable epialleles” in the offspring, with permanent phenotypic consequences:
    • Agouti viable yellow (Avy) (Waterland and Jirtle, 2003)[1]
    • Axin fused (Waterland et al., 2006) [1]

Mitogen-activated protein kinase pathway (MEK) inhibitors

  • Decrease dioctanoylglycerol-stimulated activation of lipolysis

Mléko kojenců

  • Formula-fed children drink higher volumes, which may entrain satiety differently (Taveras et al 2004)
    • Vyšší riziko obezity [1]
      • Breast-fed infants have a different gut biota
        • Oligosaccharide content of human milk (Parracho et al 2007; Boehm et al 2007) [1]
        • Biotic conversion of food may be different, leading to different absorption (Turnbaugh et al 2006) [1]
      • Bottle feeding after a period of relative constraint in fetal life merely exaggerates a mismatch
        • Short-term effects on adipose tissue development
          • Phase of metabolic and neuronal plasticity, may later manifest in greater sensitivity to fat in the diet [1]
  • Rapid weight gain during early infancy
    • Associated with susceptibility to obesity in adulthood [1]

Negative regulators of UCP-1 expression

  • Serum and mitogens that activate c-jun (Yubero et al., 1998)

Neuropeptide Y



Nicotinic receptors in WAT

  • Functional nicotinic receptor on white adipocytes [78]
    • Increased insulin sensitivity of these cells under nicotine stimulation [78]

Omega 3 FA

NF-E2 related factor-2 (NRF2)

  • Oxidative stress response factor
  • Up-regulation in response to the oxidized products of
    • Eicosapentaenoic acid - EPA
    • Docosahexaenoic acid - DHA
  • Mediating oxidative stress responses

Obezita matky v těhotenství

  • Bariatrická redukce hmotnosti před otěhotněním
    • Children born after maternal weight loss
      • Lower risk for obesity than do their siblings born before maternal weight loss (Kral et al., 2006)[1]
      • “metabolic imprinting” of body weight regulation (Waterland and Garza, 1999; Waterland, 2005) [1]

Párování obézních mezi sebou

  • Mating of biologically related individuals [1]
  • Inbreeding may be considered an extreme form of assortative mating
    • Probability of increasing the genetic predisposition to obesity in the offspring of two obese parents could be very high [1]
  • Significant spousal similarities in BMI and triceps skinfold
    • Correlations did not increase with length of marriage duration. (Knuiman et al 1996) [1]

Orexigenní vlivy


  • Jedním ze spouštěčů puberty v senzitivním období je podíl tukové tkáně v těle
    • Věk začátku puberty je nepřímo úměrně závislý na stupni prepubertálního body mass indexu (BMI) (Krás-ničanová, 2010)
    • Nadváha v kritickém období
      • Urychluje nástup menarche o 0,13 roku na navýšenou jednotku BMI (iroet al., 2006)
      • Zkracuje dětství
      • Prohlubuje rozdíl mezi biologickou a sociální zralostí

Orexigenní účinky


Agouti protein

  • Vylučován tukovou tkání (Kim and Moustaid-Moussa, 2000)
  • Může podporovat chuť k jídlu blokádou aktivity melanokortinu na Mcr4 v mozku (Voisey and Van Daal, 2002)
  • V.s. tuková tkáň u obézních lidí podporuje chuť k jídlu
    • Dietou se sníží sekrece leptinu
    • Když zůstává masa tukové tkáně konstantní, agouti protein působí stále stejně [1]

Amylin - pokles sekrece

  • Snížená sekrece se snižujícími se hladinami glukózy / selháváním sekrece inzulínu ze slinivky
  • Pocity hladu při nejezení [1]

Antagonisté melanokortinových receptorů

  • Agouti related protien
    • Blokáda vazby melanokorinu na melanokortinové receptory v ncl. arcuatus Agouti related proteinem [1]

D1

  • D1 receptory v hypotalamu podporují příjem potravy [1]

Galanin

  • Stimuluje chuť k jídlu, zvláště pro tuk
  • Produkován specializovanými neuroendokrinními buňkami v hypotalamu aj.č. CNS a GIT
  • Uvolňován spolu s prolaktinem
  • 3 receptory pro galanin v mozku a mnoha j. tkáních [1]

Ghrelin

  • Vylučován v žaludku a duodenu do krve
  • Odpověď na několik hodin půstu (Cummings a kol., 2002)
  • Sekrece se rychle zastavuje po najezení
  • Denní variabilita
    • Vzory příjmu potravy u člověka [1]
  • Průměrné cirkulující hladiny
    • Dlouhodobá regulaci příjmu potravy
  • Vyjmutí větší části tkáně během žaludeční operace (bypass)
    • V.s. i důležitý mechanismus pro trvalé snížení tělesné hmotnosti [1]

Glukózový pokles

V.s. zvýšení cirkulujících hladin inzulinu

  • Indukují chuť k jídlu a hlad (Bray, 2000) [1]

Hormon uvolňující růstový hormon

  • Zvyšují příjem potravy [1]

Chuť

  • Sekvence centrálně zprostředkovaných procesů (cefalická fáze odpovědi)
    • Stimulace exokrinní sekrece
      • Sliny
      • žaludeční kyselina
    • Stimulace endokrinní sekrece
      • Inzulin (Nederkoorn a kol., 2000) [1]

Kannabinoidy

  • G-protein-přidružené kanabinoidní receptory
    • CB1 (hlavně v mozku)
    • CB2 (hlavně v imunitních buňkách)
  • Odpovídají na
    • Endokanabinoidy
      • V.s. 2-arachidoylglycerol
      • V.s. 2-arachidonyl glyceryl ether
      • V.s. anandamid [1]
    • Několik fytochemických látek z rostliny Cannabis (Onaivi a kol., 2002)
      • Látky odvozené od konopí podporují chuť k jídlu:
        • Tetrahydrokanabinol
        • Kanabidiol (není psychotropní)
        • Delta-9-tetrahydrokanabinolu
          • Potlačení nevolnosti a zvracení
            • U pacientů s nádorovým onemocněním a AIDS
              • Zlepšení touhy po příjmu potravy (Mechoulam and Hanu, 2001) [1]
  • V.s. inhibice uvolnění neurotransmiteru cílovými neurony [1]

Melanin-koncentrující hormon (MCH)

  • Cyklický malý neuropeptid
  • Z laterální hypotalamické oblasti a nucleus arcuatus
  • Podporuje příjem potravy
  • Působí aktivaci G-protein-přidruženého MCH receptoru 1 (Marsh a kol., 2002)
  • V.s. aktivuje i NPY Y1 receptory (Chaffer and Morris, 2002) [1]

NPY/AgRP neurony v nucleus arcuatus

  • Produkují
    • Neuropeptid Y (NPY)
    • Agouti-related protein (AgRP)
      • AgRP specificky blokuje vazbu melanokortinu na Mc4r a Mc1r a Mc3r
        • Zvyšuje chuť k jídlu
  • Stimulovány ghrelinem
    • Signalizuje prázdný žaludek [1]
  • Když se do mozku dostává méně inzulinu
    • NPY neurony aktivnější
      • Stimulují centrum pro chuť k jídlu [1]

Opioidní peptidy

  • Zvyšují příjem potravy [1]

Orexiny

  • Produkovány neurony v laterálních, dorsomediálních a perifornikálních oblastech hypotalamu blízko báze stopky hypofýzy
  • Peptidy podporující chuť k jídlu
  • Orexin A = hypokretin 1
  • Orexin B = hypokretin 2
    • Ze stejného prekurzoru [1]
  • Neurony produkující orexiny
  • Orexiny stimulují chuť k jídlu aktivací opioidních receptorů (Clegg a kol., 2002)[1]
  • Ovlivňují nespavost a další typy chování (Shirasaka a kol., 2002) [1]

Receptory na glukózu ve ventromediálním hypotalamu

  • Mozku informace o koncentracích glukózy v krvi (Ngarmukos a kol., 2001)[1]

Sůl

  • Nedostatek soli - bažení po slaných jídlech
    • částečně zprostředkován angiotenzinem I syntetizovaným v CNS (McKinley a kol., 2001)
  • Více z přednastaveného upřednostňování slaného
  • Nadměrný příjem soli, deplece tekutin a žízeň
    • Averze k soli (Thunhorst and Johnson, 2001)

Vizuální podněty

  • Cefalická fáze odpovědi [1]


Literatura:

[1] KOHLMEIER M., NUTRIENT METABOLISM. ACADEMIC PRESS, LONDON, 2003, 826 PP. ISBN 0-12-417762-X, STR. 25-30. Regulace příjmu potravy. Chuť k jídlu. URL < appetitestop.cz/pdf/regulace.pdf >.

Orexin A


Orexin

  • In the lateral hypothalamus
  • Stimulates food intake as well
  • In rodents, orexin levels are increased by sleep deprivation
  • Decreased with recovery sleep (Pedrazzoli et al., 2004) [1]

Organontin endocrine disruptors

  • Agricultural fungicides
  • Rodent repellents
  • Molluscicides
  • Antifouling paints for ships and fishing nets

Nuclear Receptors (NR) agonists

  • High affinity agonists
    • PPAR-gamma [1]
    • Retinoic acid X receptor (RXR) (Kanayama et al 2005)[1]

Nuclear receptor antagonists

Ovariectomy

  • Ovariectatomied (Ovx) mice and Syrian hamster increases WAT [1]
  • Ovariektomie in 8-week old female Wistar rats induced hyperphagia
    • Effects were fully reversed by subcutaneous E2 replacement [2]
  • E2 effects on adipose tissue are predominately through ER-alfa [2]
  • Nuclear and mitochondrial pools of ER-alfa may be responsible for E2 regulation of body weight and obesity [2]
  • Detected in mitochondria of
    • HepG2
    • MCF-7 cells
    • Rat cerebral blood vessels [1]

Rodents after Ovx

  • Factors in energy expenditure were lower
    • ERR1
    • PPAR
    • PGC1
    • PGC1-beta [1]
  • MRNA levels of the enzymes for fatty acid beta-oxidation were lower in adipose tissue and skeletal muscle:
    • Medium-chain acyl-CoA dehydrogenase
    • Acetyl-CoA oxidase [1]
  • Decreased expression of transcription factors important for lipogenesis
    • PPAR-gamma
    • SREBP1
    • Acetyl CoA carboxylase
    • Fatty acid synthase [1]
    • Diacyl glycerol acetyl transferase 1 and 2 [1]

Polycystic ovarian syndrome (PCOS) associated with

  • Insulin resistance
  • Glucose intolerance
  • Subsequent T2D
  • Most common endocrine disorder in reproductive age women [51]
  • Inadequate acute insulin release to the degree of insulin resistance
  • Exaggerated early insulin response to glucose
    • Not accounted for by insulin resistance
    • Closely associated with hyperandrogenicity [51]
  • Robust relationship between ß-cell function and free testosterone
    • Excess testosterone in women leads to insulin hypersecretion [51]
  • Accompanied by systemic oxidative stress [51]
  • High circulating androgens [52]
  • Originate from ovaries and adrenals
  • Frequently suffer from the metabolic syndrome including obesity
  • Simple obesity - androgen synthesis within adipose tissue
  • Expression of 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) isozymes
    • Effcient conversion of androstenedione to testosterone in both subcutaneous and omental fat
    • Whole fat
      • 17beta-HSD5 and 4
    • Preadipocytes of subcutaneous and omental origin
      • 17beta-HSD5 and 4
      • Increase in 17-beta-HSD5 expression upon differentiation of stromal preadipocytes to mature adipocytes [52]
    • Subcutaneus fat
      • Higher expression of 17beta-HSD5 než v omentu
      • Aktivita increased with differentiation
  • Androgen inactivation

PNS innervation

  • Increases insulin sensitivity in WAT [78]

Podvýživa

  • Fetal undernutrition and postnatal leptin administration
  • Induce persistent changes in DNA methylation and expression of hepatic genes (Gluckman et al., 2007c) [1]

Pokles sympathetic nervous tone

  • Některé případy obezity dospělých lidí which a decreased sympathetic activity
  • Decreased sympathetic activity in childhood obesity [78]
  • Desinhibition of adipocytes proliferation and differentiation [78]
  • Recruitment of new precursors
  • Appearance of new adipocytes [78]
  • Decreased lipolysis
  • Influence of hyperinsulinemia
    • Favor hypertrophia [78]
  • Decreased thermogenesis
    • Pokles aktivity UCP1
    • Pokles počtu brown adipocytes [78]
      • Decreased proliferation and differentiation
      • Increased apoptosis [78]

Chemical polutants

  • Chemical pollutants, are now considered contributing factors for insulin resistance
  • Most of chemical pollutants potentially accumulate into adipose tissue
  • “environmental obesogen hypothesis”
    • Associated to the adipose tissue inflammatory phenotype
      • Major contributing factor for the decreased insulin sensitivity [68]
  • Synthetic chemical lipophilic pollutants
    • Pesticides
    • Organophosphates
    • Polychlorinated bisphenyls
    • Phthalates
    • Solvents etc. [68]
  • Diet, the air and the ground
  • Those which are resistant to biological and chemical degradation
    • Persistent Organic Pollutants(POPs) [68]
      • Most of them also classified as endocrine disruptors [68]


Polycystic ovary syndrome


Gen APOA2

  • Někteří lidé vlivem nasycených tuků přibírají rychleji než jiní
    • Ještě negativnější účinky na lidi, kteří vlastní nepříznivou variantu genu APOA2
      • Při nadměrné konzumaci nasycených tuků riziko vzniku nadváhy dvojnásobné
      • Snížením příjmu nasycených tuků může dojít
        • K snížení jejich BMI o 4 kg/m2
  • Cca 37 % lidí v populaci je homozygot pro výhodné varinaty APOA2
DM má 2 příznivé kopie genu APOA2
  • reaguje na nasycené tuky normálním způsobem
    • dle výsledky Life testu

Postmenopausal women

  • Have increased WAT
  • ERT restores WAT to lower levels (Tchernof et al 1998) [1]
  • estrogen therapy has positive effects on carbohydrate and lipid metabolism in overweight-obese younger postmenopausal women [2]

PPAR gamma 2

  • Activation
    • Induces the differentiation of mesenchymal cells into adipocytes [80]

The mice with targeted deletion of PPAR gamma 2

  • Insulin resistance
  • PPAR gamma 2 is necessary for the maintenance of insulin sensitivity (Medina-Gomez et al., 2005) [80]

PPAR-gamma agonists

  • Efficiently promote adipocyte differentiation from pre-adipocytes (Kanayama et al 2005) [1]
  • Activated receptors (PPARs) which play a major role in adipocyte differentiation and energy storage [2]

PPAR gamma

  • In adipose tissue
  • Activated by fibrate
    • Regulates lipid catabolism
  • During adipogenesis activated (Tontonoz et al., 1995) [80]
  • Ectopic expression of PPAR gamma
    • Induces differentiation into adipocytes upon the stimuli of PPAR gamma agonists
      • Thiazolidinediones
      • Glitazones (Tontonoz et al., 1995) [80]

PPAR gamma knockout mice

  • Alterations with opposite results in some studies
    • Reduced fat formation
    • Protection against obesity
    • Insulin resistance with lipodystrophy (Jones et al., 2005) [80]

PPARs

  • Nuclear receptors
  • Transcription factors
  • Regulate gene expression through nutritional stimuli
  • Activate the PPAR response elements (PPRE)
    • Present in the promoter of specific target genes
    • Form heterodimers with the X receptor of retinoic acid (RXR)
  • PPREs
    • In their promoters
      • FAS, aP2, PEPCK, LPL, SCD
    • Can bind different isoforms in different tissues
  • Roles in
    • Adipogenesis
    • Inflammation
    • Atherogenesis
    • Glucose homeostasis
    • Cancer [80]
  • PPAR delta and PPAR gamma
    • Quite specific of adipose tissue

Prader Willi syndrome (PWS)

  • Hyperphagic obesity
  • Lack of paternal expression of genomically imprinted genes on chromosome 15q11-q13 [1]
  • Most PWS [1]
    • Paternal deletion [1]
  • Cca 25% of cases
    • Maternal uniparental disomy
      • Inheriting both copies of chromosome 15 from the mother (Goldstone, 2004)
        • no genetic lesion in these cases
        • Inappropriate epigenetic silencing of both copies of the 15q11-q13 region leads to obesity [1]

Preadipocytes from obese people

  • Produce mitogenic factors
    • Induce a higher proliferation rate than those produced by control subjects (Lau et al., 1987) [80]

Preadipocytes

  • Mesenchymal-type cells
  • In the stroma-vascular fraction (SVF) of the adipose tissue
  • Precursor cells
  • Proliferate and differentiated in culture [80]

Prednisone



Příkrmy

  • An artificial high-carbohydrate but low-fat diet in the pre-weaning period causes obesity in rats (Srinivasan et al 2003)
    • As does maternal gestational diabetes (Franke et al 2005) [1]
    • Can be mimicked by neonatal administration of insulin (Harder et al 1998) [1]
    • Protective effects of neonatal leptin treatment (Vickers et al 2005)[1]
  • Importance of the neonatal period in the programming of obesity, at least in rodents [1]

Pro-adipogenic Ppar gamma transcription factor Krüppel-like factor 9 - Klf9


Proopiomelanocortin - POMC mutations

  • Monogenic obesity in humans (Rankinen et al., 2006) [1]
  • Epigenetická regulace transkripce [1]

Protease inhibitors

  • Antiretroviral therapy and protease inhibitors anti HIV regimens

Dietary PUFAs

  • Interact with sterol regulatory element binding protein (SREBP)
  • Transcription in the liver is involved in the regulation of genes related to
    • Synthesis and uptake of cholesterol
    • Fatty acids
    • Phospholipids
  • SREBPs are implicated as early mediators of insulin responses

Původ preadipocytů

  • Pluripotential stem cells give rise to preadipocytes
  • A mesenchymal cell predetermined to be adipocyte
  • Common mesenchymal stem cell produces
    • Adipocytes,
    • Myoblasts
    • Osteoblasts [80]

ROS

  • Effect of chronic inflammation-induced excessive ROS or oxidative stress on the development of obesity
  • Human visceral fat depot
    • Unique inflammatory profile
    • May directly contribute to chronic systemic inflammation in obese humans
  • Lowering the levels of ROS or oxidative stress
    • Becomes an important strategy to deal with obesity-related alteration [20]

Rous-associated virus-7 (RAV-7)

  • Avian retrovirus

Kuřata

  • Stunted growth, obesity and hyperlipidemia in chickens (Carter et al 1983a & b) [1]
  • Decreased thyroid hormone levels (Duff et al 1969) [1]

Selekční výhoda pro rozmnožování

  • USA - individual’s BMI is significantly and positively related to the number of offspring that the individual has produced (Weng et al 2004; Bastian et al 2005; Rosenberg et al 2003) [1]
    • Min. 1 dítě between baseline measurement and the 4 years to follow-up
      • Gained more weight (~4.4 kg) than women s 0 dětmi (Rosenberg et al 2003) [1]
  • The magnitude of the associations of parity to overweight was greatest in
    • North Africa/West Asia
    • Latin America
    • Caribbean regions [1]
  • Positively correlated with levels of country development [1]
    • Effect of mild-to-moderate obesity on fecundity may be positive [1]
      • Obesity in women is associated with lower socioeconomic status (Lipowicz, 2003), which has been linked to producing more offspring (Salihu et al., 2004)[1]
      • Women that are too lean suffer impaired fertility (Frisch, 1987) [1]
  • V jiné studii korelovalo normální BMI v pubertě s vyšším počtem potomků [1]





Saturated Fatty Acids - SFAs

  • Can induce pro-inflammatory signaling
  • Interactions of saturated fatty acids are still rather ambiguous in many areas
  • Varying physiological effects
  • Relationship between SFA intake and cardiovascular disease, an inflammatory condition
  • Impact of a SFA diet versus a monounsaturated fatty acids (MUFAs) diet on gene expression in adipose tissue
    • SFA diet led to an overexpression of genes involved in inflammatory processes
      • Upregulation of cathepsin S (CTSS)
      • Interleukin-8 (IL-8)
      • Integrin beta 2 (ITGB2) in moderately overweight individuals
        • Profile was similar to that found in obese Pima Indians [38]

Long-chain saturated fatty acids

  • Typically cited for their harmful effects to
    • Endothelial cells [38]

Myristate

Palmitate

  • Can induce apoptosis via NFkappaB induction in human coronary artery endothelial cells (HCAECs)
  • Can induce pro-inflammatory endothelial cell phenotypes
    • Incorporation into endothelial cell lipids
    • Short- and medium-chain SFAs do not incorporate or cause lipotoxicity [38]

Stearic acid

  • Induced an up-regulation of ICAM-1 human aortic endothelial cells (HAECs) in an NFkappaB dependent manner [38]

Lauric acid and palmitic acid

  • Did not activate TLR2 and TLR4 in HEK-Blue cells transfected with TLR2 and TLR4
  • Another study investigators found that did activate TLR2 and TLR4 in RAW264.7 macrophages and transiently transfected THP-1 monocytes [38]

Medium-chain SFAs

  • Provide beneficial health effects
  • Including suppression of body fat accumulation and obesity [38]

Složení stravy obezitogenni vlivy již v kojeneckém věku

Mléko kojenců

  • Formula-fed children drink higher volumes, which may entrain satiety differently (Taveras et al 2004)
    • Vyšší riziko obezity [1]
      • Breast-fed infants have a different gut biota
        • Oligosaccharide content of human milk (Parracho et al 2007; Boehm et al 2007) [1]
        • Biotic conversion of food may be different, leading to different absorption (Turnbaugh et al 2006) [1]
      • Bottle feeding after a period of relative constraint in fetal life merely exaggerates a mismatch
        • Short-term effects on adipose tissue development
          • Phase of metabolic and neuronal plasticity, may later manifest in greater sensitivity to fat in the diet [1]
  • Rapid weight gain during early infancy
    • Associated with susceptibility to obesity in adulthood [1]

Příkrmy

  • An artificial high-carbohydrate but low-fat diet in the pre-weaning period causes obesity in rats (Srinivasan et al 2003)
    • As does maternal gestational diabetes (Franke et al 2005) [1]
    • Can be mimicked by neonatal administration of insulin (Harder et al 1998) [1]
    • Protective effects of neonatal leptin treatment (Vickers et al 2005)[1]
  • Importance of the neonatal period in the programming of obesity, at least in rodents [1]

Fruktóza

  • High-Fructose Corn Syrup Consumption (HFCS)


SMAM-1

Kuřata

  • 53% increase in visceral fat in three weeks after inoculation (Dhurandhar et al 1990; 1992) [1]
  • Horizontal transmission - visceral adiposity [1]
  • Reduction in serum cholesterol and triglycerides [1]
    • Tuková tkáň získala větší kapacitu = oddálení projevů metabolického syndromu

K. močová, sodík, voda a obezita

Uric Acid - A KEY Cause of Weight Gain, Diabetes, Heart Disease & Dementia (Dr. David Perlmutter)


Epidemiologie

  • Increased incidence of obesity with decreased amount of sleep in the population over the last 40 years [1]
  • National Sleep Foundation (NSF) suggest that American adolescents and adults are chronically sleep deprived (Bonnet and Arand, 1995; Broman et al., 1996; NSF, 2008; Wolfson and Carskadon, 1998; Spiegel et al., 1999) [1]
  • Americans slept
    • Before World War I: 8.7 - 9 h (Terman and Hocking, 1913; Tune, 1968) [1]
    • About 30 years ago: 7.68 h (Bliwise, 1996)[1]
    • 2004 74.4% of 1000 adults: less than 8h (Taheri et al., 2004)
    • NSF 2008 adults average: 6 h 40 min per weeknight
      • 44% of adults less than 7 h a night
      • Short sleepers (less than 6 h a night on workdays)
        • Significantly more likely to be obese than those that self-reported to be normal or long sleepers (8 hours or more on workdays)

Výchova

  • Children have later bedtimes but their morning waking time has stayed constant
    • More liberal parental attitudes (Iglowstein et al., 2003) [1]

Délka spánku

  • Biological mediators of appetite and energy homeostasis may be affected by sleep duration. [1]
  • Diabetes
    • Associated with 5 or less hours/day and long sleep duration 9 or more hours/day [1]
  • BMI
    • Tend to be higher among the short-sleepers only (Ayas et al., 2003) [1]

Spánková deprivace

  • Sleep debt exerts profound effects on metabolic hormones.
    • Increased food intake
    • Incr. energy storage
    • Development of diabetes and heart disease (Gottlieb et al., 2005; Spiegel et al., 2005; Bjorvatn et al., 2007; Flint et al., 2007; Knutson et al., 2007; Trenell et al., 2007; Van Cauter et al., 2007) [1]

4h spánku 2x po sobě

  • Young men 4h (x 10h spánku)
  • Plasma leptin levels were decreased 18% (Spiegel et al., 2004b) [1]
  • 28% increase in plasma ghrelin [1]
  • Ratings of hunger and overall appetite increased 24% - 23% [1]
    • Energy-dense, high-carbohydrate foods greatest increase (Spiegel et al., 2004b) [1]

4h spánku 6x po sobě

  • Young men
  • 40% decrease in the rate of glucose clearance
  • 30% reduction in insulin response and glucose effectiveness (Van Cauter and Spiegel, 1999) [1]

8 days 5h spánku / 14 dní restrikce o 1,5h spánku

  • Similar effects on glucose and insulin parameters (Knutson et al., 2007) [1]
  • Diabetic-like glucose/insulin profile
    • Increase adiposity and weight gain (Knutson et al., 2007) [1]
  • Significant associations between diabetes and reduced sleep (Gottlieb et al., 2005; Spiegel et al., 2005; Flint et al., 2007; Trenell et al., 2007) [1]

5h spánku chornicky

  • 15.5% lower leptin levels (x spánku 8h chronicky) (Taheri et al., 2004) [1]
  • Less than 6 or 7 hrs a night = higher mortalilty rates (Heslop et al., 2002; Kripke et al., 2002) [1]
    • Mildly decreased sleep (generally to 6–7 hours/day) and lower mortality rates (Alvarez and Ayas, 2004; Youngstedt and Kripke, 2004) [1]

Parciální sleep deprivation

  • Pokles TSH hladin i sekrece
    • I přes to, že E intake and activity levels constant (Spiegel et al., 2004a; Knutson et al., 2007) [1]
  • Tiredness, tiredness decreases activity, and decreased activity
    • Contributes to weight gain (Taheri, 2007) [1]


Insomnie

  • Linked genetic contributions of insomnia, sleepiness, and obesity [1]

Spánková deprivace hlodavců

  • Increase in food intake [1]
    • Researchers frequently use the hyperphagia to gauge sleep deprivation intensity [1]
  • Orexin levels are increased [1]

Potkani spící pouze 5h

  • Plasma ghrelin levels ++
  • Food intake ++ (Bodosi et al., 2004) [1]

Potkani spánková deprivace 16 dní

  • Leptin significantly suppressed
  • Feeding increased (Everson and Crowley, 2004) [1]
  • Galanin mRNA increased in brains (Lu et al., 2005) [1]

Spánková apnoe

  • Increased plasma neuropeptide Y levels
    • Independently of body weight (Tasali and Van Cauter, 2002; Barcelo et al., 2004) [1]

Literatura:

[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.

Spánková deprivace

  • .meta.jpg
  • .meta2.jpg


Sterol-regulatory binding protein 1c


Střevní mikroflóra

  • Metabolickou výkonnost rovnocennou jaternímu metabolismu (Macfarlane a Macfarlane, 1997) [5]
  • Podílí se na metabolismu živin a její skladba jej významně ovlivňuje (Korner a Leibel, 2003)[5]
  • Zdroj prvotního osídlení střeva
    • Mikroflóra rodičky při průchodu porodním kanálem (Rigon et al., 2012) [5]
    • Mateřské mléko
      • 103 kultur ze střevní mikroflóry/1 ml (Perezet al., 2007) [5]
  • Novorozenci z císařského řezu
    • Mohou mít až 1,5x vyšší riziko obezity (Kuhle et al., 2015) [5]

Obézní jedinci a složení střevní mikroflóry:

  • Menší podíl
    • Kmenu Bacteroidetes [5]
  • Větší podíl: [5]
    • Firmicutes [5]
  • Sníženou celkovou bakteriální rozmanitost (Turnbaugh et al., 2009) [5]

Ob/Ob myši

  • Higher relative abundance of the firmicutes vs the bacteriodetes [1]
    • Reverse was true in the microbiota population of lean mice [1]

Myši se sterilním střevem

  • Osídlení střevní mikroflórou
    • Increases their body fat by 60% [1]
    • Induces insulin resistance (Backhed et al 2004)[1]
    • Despite the lower food intake in this group [1]
    • Increased harvest of monosaccharides from the gut
    • Vzdestup hepatic de novo lipogenesis
    • Potlačení produkce střevním epitelem:
      • Fasting-induced adipocyte factor (Fiaf)
      • Lipoprotein lipase (LPL) inhibitor [1]
        • Disinhibition of LPL
          • Increase triglyceride storage in adipocytes [1]
  • Gut of germ-free mice with microbiota of Ob/Ob mice
    • Significantly increased level of total body fat than their germ-free counterparts colonized with microbiota from genetically lean mice (Turnbaugh 2006)[1]

Strumigeny


Sulfonylureas


Svědivka / svrbivka - scrapie agents

Myši

  • Induces obesity in mice (Kim et al 1987; Carp et al 1998) [1]
  • Disrupt normal glucose metabolism
  • Hyperglycemia resulting in disrupted transvascular glucose transport in some regions of the brain (Vorbrodt et al 2001)
  • May lead to functional dysregulation of hypothalamus and consequential adiposity [1]

Sympathetic efferent fibers synthetize and release

NPY

  • Stimulates fat angiogenesis
  • Proliferation and differentiation of new adipocytes
    • Adipose tissue growth [78]
  • Mediated through Y1 and/or Y2 receptor subtypes
    • Antagonize or minimize NE effects [78]

Tamoxifen (TAM)

  • Anti-estrogen
  • Attenuated the effects of E2 on reducing body weight [2]
  • Hepaticsteatosis is a frequent complication [1]
  • Impaired hepatic FA beta-oxidation in liver
    • Peroxisomes
    • Microsomes
    • Mitochondria [1]
  • Progression of massive hepatic steatosis in estrogen deficiency
    • Potentially serious
      • 3% USA = nonalcoholic steatohepatitis by obesity and hyperlipidemia [1]



Higher ambient temperature

  • Cessation of the thermogenic activity in the tissue
  • Rapid degradation of RNA and proteins
  • Decreasing mitochondrial content
  • Decreasing the amount of nuclear DNA in the tissue
  • Eventually the BAT mass is decreased [78]

Okolní teplota teplejší

  • Historical increase in ambient temperature may have had subtle, yet significant effects on metabolic rate and consequently, weight gain [1]
  • Influencing postnatal weight gain
  • Environment during infancy on the risk of late-life obesity and diabetes (Strauss et al 1997)
  • Adolescents aged 15–19 years old
    • Females with a BMI > 85th percentile tended to be born during warmer ambient temperatures (>13.2°C)
      • Only statistically significant for African American females (van Hanswijck de Jonge et al 2002) [1]
  • One week-old infants placed in an incubator at 36.5°C for two weeks
    • Greater increases in body weight and length compared to a group of infants placed in an incubator maintained at 35°C (Glass et al 1968)
  • Weight gain during the first four months of life
    • Positively correlated with childhood overweight status (Stettler 2002)[1]
  • Infants born in the spring (in warmer ambient temperatures)
    • Vyšší + váhy
    • Significant for Puerto Rican and African Americans (van Hanswijck de Jonge et al 2003) [1]
  • 22 versusu 16°C v místnosti
    • Rozdíl v energy expenditure o
      • 167 kcal / day u mužů i žen (Westerterp-Plantenga et al 2002; Buemann et al 1992) [1]
      • 23 kcal / day [1]
      • 239 kcal / day (van Marken Lichtenbelt et al 2001)[1]
      • 185 kcal day-1 (Westerterp-Plantenga et al 2002) [1]
  • Decreasing energy intake, exposure to high ambient temperatures also increases metabolic rate
    • Core body temperature is elevated
    • Metabolic rate increases by 7–17% per °C rise in body temperature (Saxton et al 1981) [1]
    • Increased use of air conditioning is likely to lead to a positive energy balance by increasing energy intake while reducing energy expenditure [1]

Literatura:

[1] Ten Putative Contributors to the Obesity Epidemic. URL < www.ncbi.nlm.nih.gov/pmc/articles/PMC2932668/?tool=pmcentrez >.


Vyšší hladina testosteronu u žen

  • Higher levels of free testosterone and lower levels of SHBG
    • Repeatedly associated with
      • Glucose intolerance
      • Insulin resistance in women [51]
  • High free testosterone levels are associated with
    • Higher risk of T2D in women [51]
  • Increases visceral adiposity in females [51]

Thiazolidinediones


Transcriptional factor sterol regulatory element-binding protein 1c (SREBP-1c)

  • Enhances lipogenesis and adipogenesis

Transferrin

  • White preadipocytes
  • Require to proliferate in serum-free medium
      • T3
      • Insulin
      • Transferrin (Deslex et al., 1987a,b) [80]

Transforming growth factor- b 1

  • Potent mitogen in the same culture system [76]

Tributyl tin

  • Developmental exposure is associated with obesity or overweight and adipogenesis

Adipose tissue

  • Is a source of several growth factors that could stimulate proliferation
    • IGF-I
    • IGF binding proteins
    • TNF alpha
    • Angiotensin II
    • MCSF (Hausman et al., 2001, 2008) [80]

Umělá sladidla

Vznik obezity a diabetu

  • Stimulují chuť na sladké - mozek - střevo - +Ghrelin hormon hladu ze střeva
  • Slinivka vyloučí inzulín
    • Cukr nepřišel - hlad

Valproate [Depacon, Depakene]


Věk matky

  • The mean pregnancy age has steadily increased throughout the world (Nabukera et al., 2006; Mathews and Hamilton, 2002) [1]
  • Vliv na attention given to children
  • The type of diet provided
  • Amount of physical activity encouraged
  • Maternal age itself might be a contributor to escalating rates of obesity has been neglected [1]
  • Mothers of obese children were on average 3.5 years older at the time of birth than the mothers of normal-weight children (Wilkinson et al., 1977) [1]
  • Higher maternal age at birth increase body fat percentage at age seven in the offspring [1]
    • Women 30 years of age or older
      • Children´s body fat composition 2.6 to 2.8 absolute percentage points higher than that of children´s born to women younger than 25 (Blair et al., 2007) [1]
  • Each 5-year increment in maternal age increased the likelihood for obesity by more than 14% v grafu
    • Girls born to women over 25 years of age, the risk for childhood obesity is increased by nearly a third
    • Girls born to mothers 30 and over, the risk is nearly double (Patterson et al., 1997) [1]
  • Older women are at risk for giving birth to infants at both ends of the birthweight distribution, i.e., both large and small for gestational age.
    • Both of these groups are more likely to develop obesity. [1]
    • Vliv maternálních komorbidit especially older first time mothers, gravidas (Hardy et al., 2003) [1]
      • Pre-eclampsia
      • Hypertension
      • Fetal growth restriction
      • Obesity, insulin resistance
      • Hypertension

Animal models and epidemiologic investigations

  • Direct and independent association between maternal age and obesity in offspring [1]

UCP1

  • Key role in energy expenditure and thermogenesis
  • Brown adipose tissue metabolism (Hansen and Kristiansen, 2006; Ricquier, 2005) [1]
  • At 1 year of age, sheep born to adult mothers
    • Increased fat deposition compared with those born to juvenile ewes [1]
    • First time mothers
      • Greater overall adipose tissue accretion
      • Accelerated loss of brown adipose tissue metabolism
      • Decline in tissue-specific UCP1 [1]

Věk

  • Ectopic fat accumulation occurs in
    • Bone marrow
    • Muscle
    • Liver
  • Possibly contributes to age-related dysfunctions of these tissues (Rasouli et al., 2007) [54]
  • Androgens and oestrogens have been implicated in regulating ectopic fat deposition and regional fat distribution [54]

Visfatin

  • Orexigenic effect
  • Positive correlation between plasma visfatin level and
    • Body fat mas
    • Body weight in human [74]

Vyšší okolní teplota

  • Historical increase in ambient temperature may have had subtle, yet significant effects on metabolic rate and consequently, weight gain [1]
  • Influencing postnatal weight gain
  • Environment during infancy on the risk of late-life obesity and diabetes (Strauss et al 1997)
  • Adolescents aged 15–19 years old
    • Females with a BMI > 85th percentile tended to be born during warmer ambient temperatures (>13.2°C)
      • Only statistically significant for African American females (van Hanswijck de Jonge et al 2002) [1]
  • One week-old infants placed in an incubator at 36.5°C for two weeks
    • Greater increases in body weight and length compared to a group of infants placed in an incubator maintained at 35°C (Glass et al 1968)
  • Weight gain during the first four months of life
    • Positively correlated with childhood overweight status (Stettler 2002)[1]
  • Infants born in the spring (in warmer ambient temperatures)
    • Vyšší + váhy
    • Significant for Puerto Rican and African Americans (van Hanswijck de Jonge et al 2003) [1]
  • 22 versusu 16°C v místnosti
    • Rozdíl v energy expenditure o
      • 167 kcal / day u mužů i žen (Westerterp-Plantenga et al 2002; Buemann et al 1992) [1]
      • 23 kcal / day [1]
      • 239 kcal / day (van Marken Lichtenbelt et al 2001)[1]
      • 185 kcal day-1 (Westerterp-Plantenga et al 2002) [1]
  • Decreasing energy intake, exposure to high ambient temperatures also increases metabolic rate
    • Core body temperature is elevated
    • Metabolic rate increases by 7–17% per °C rise in body temperature (Saxton et al 1981) [1]
    • Increased use of air conditioning is likely to lead to a positive energy balance by increasing energy intake while reducing energy expenditure [1]

Věk matky

  • The mean pregnancy age has steadily increased throughout the world (Nabukera et al., 2006; Mathews and Hamilton, 2002) [1]
  • Vliv na attention given to children
  • The type of diet provided
  • Amount of physical activity encouraged
  • Maternal age itself might be a contributor to escalating rates of obesity has been neglected [1]
  • Mothers of obese children were on average 3.5 years older at the time of birth than the mothers of normal-weight children (Wilkinson et al., 1977) [1]
  • Higher maternal age at birth increase body fat percentage at age seven in the offspring [1]
    • Women 30 years of age or older
      • Children´s body fat composition 2.6 to 2.8 absolute percentage points higher than that of children´s born to women younger than 25 (Blair et al., 2007) [1]
  • Each 5-year increment in maternal age increased the likelihood for obesity by more than 14% v grafu
    • Girls born to women over 25 years of age, the risk for childhood obesity is increased by nearly a third
    • Girls born to mothers 30 and over, the risk is nearly double (Patterson et al., 1997) [1]
  • Older women are at risk for giving birth to infants at both ends of the birthweight distribution, i.e., both large and small for gestational age.
    • Both of these groups are more likely to develop obesity. [1]
    • Vliv maternálních komorbidit especially older first time mothers, gravidas (Hardy et al., 2003) [1]
      • Pre-eclampsia
      • Hypertension
      • Fetal growth restriction
      • Obesity, insulin resistance
      • Hypertension

Animal models and epidemiologic investigations

  • Direct and independent association between maternal age and obesity in offspring [1]

UCP1

  • Key role in energy expenditure and thermogenesis
  • Brown adipose tissue metabolism (Hansen and Kristiansen, 2006; Ricquier, 2005) [1]
  • At 1 year of age, sheep born to adult mothers
    • Increased fat deposition compared with those born to juvenile ewes [1]
    • First time mothers
      • Greater overall adipose tissue accretion
      • Accelerated loss of brown adipose tissue metabolism
      • Decline in tissue-specific UCP1 [1]

Výživa matky v těhotenství

  • Obzvláště proteiny [1]
  • ‘predictive adaptive responses’ (Gluckman et al 2005a)
  • Organism anticipates a future lower nutritional environment
  • Coordinated responses which will maximize reproductive fitness
    • Tendency to prefer a high fat diet
    • Hyperphagia
    • Less investment in muscle mass
    • Tendency to visceral adipose stores when excess energy available (Gluckman et al 2004b; Gluckman et al 2007b) [1]
  • no consequence in a nutritionally limited environment
    • Preagricultural history [1]
  • Likely to lead to mismatch in modern environments
    • Obesity [1]
  • Gestational weight gain
    • Irrespective of pre-pregnancy body mass
    • Positively associated with obesity at 3 years (Oken et al 2007) [1]

Neuroplasticita arcuate and paraventricular nuclei

  • Hypothalamus integrates signals of nutrient availability
    • Control feeding behavior
      • Via secretion of orexigenic and anorexigenic neuropeptides (Mühlhäusler 2007)
      • Plastic in early life
        • Affected by nutritional factors
          • Maternal or fetal hyperglycemia
          • Maternal overfeeding during pregnancy
          • Postnatal overfeeding of the offspring (Davidowa et al 2004) [1]

WAT denervation

  • Surgical or pharmacological denervation of WAT
    • Triggers significant increase in the number of white preadipocytes and adipocytes
    • One week after denervation of one retroperitoneal fat pad
      • DNA content is increased without change in the number of mature white adipocytes
      • Amount of A2COL6, an early marker of white adipocyte differentiation is enhanced [78]
    • One month later
      • Number of mature (small) adipocytes is significantly increased
      • Increase in the number of small adipocytes [78]

Whitening

  • Warm exposure
  • Ageing
  • Obesity
  • Significant reduction in the density of parenchymal noradrenergic nerve fibres in the adipose organ
    • Different gene expression profiles in brown adipocytes

Zeranol

Chemické vlastnosti

  • Beta-resorcylic acid lactone
  • Mycotoxin
  • From fungi of the Fusarium family
  • One of the six growth promoters
  • Approved by the FDA
  • Widely used in feedlot beef production in the US, Canada and other countries
  • Its precursor, zearalenone [67]

Rizika

Estrogenní účinky

  • Enhances the proliferation of pre-adipocytes in beef heifers [67]
    • In 2 months of Z-implants - cca 12-fold that observed in control heifers [67]
  • The pre-adipocytes isolated from Z-implanted heifers
    • More sensitive to treatment with Z and E. Z:
      • Up-regulated the expression of cyclin D1
      • Down-regulated p53 [67]
  • Implantation of Z
    • Increases body weight gain by enhancing growth of pre-adipocytes [67] [67]
  • Epidemiological studies have suggested that there are many risk factors associated with breast cancer

RF pro Ca prsu

  • Quantity of dietary fat consumed
    • Does affect human breast cancer cell growth [67]
    • Expression of the metastatic phenotype
    • Dietary fat intake and reduced survival confirmed in both postmenopausal and premenopausal breast cancer patients
    • Well established risk factor is estrogen agonists, non-steroidal zeranol (Z) [67]
  • estrogenic activity of Z was higher than that of zearalenone in stimulating the growth of cultured MCF-7 cells [67]
  • Z was able to occupy the ligand-binding domain of human estrogen receptor alpha and beta (ER? and ERß)
    • In a strikingly similar manner to estradiol-17ß (E2) [67]
  • Long-term exposure to either Z or E2 can induce
    • Transformation of human breast epithelial MCF-10A cells with similar potency
      • V.s. oxidation-reduction (redox) pathway
      • ER ß-mediated pathway [67]
  • E2 and Z have the ability to
    • Suppress:
      • MRNA expression of the estrogen-regulated candidate tumor suppressor gene by 80%
      • protein tyrosine phosphatase ? (PTP?) in primary cultured human normal breast tissues [67]
  • Up-regulate:
    • protein disulfide isomerase 5-fold
      • A potential cancer marker
      • In primary cultured normal human breast epithelial cells when exposed to Z [67]
  • The European Union
    • Prohibited the import of beef products from the US or Canada where Z serves as a growth promoter [67]


O úroveň výše

Poslední aktualizace: 26. 1. 2024 1:28:19