Hnědá - bílá tuková tkáň
Beige or brite (brown + white) adipocytes
- Third type of adipocytes
- Type of adipocytes of intermediate characteristics
- Between the white and the brown [6]
- Have UCP-1 expression
- Increase thermogenesis [6]
- Stimulated by:
- Cold
- ß3-adrenergic activators [6]
- Browning
- Development of brite adipocytes within white adipose tissue depots
- Especially subcutaneous ones [6]
- Probably from the same precursor cell of the white adipocytes
- Induction of browning in white adipose tissue
- Could be an effective strategy
- To increase lipid metabolism
- Improve obesity and type 2 diabetes [6]
- Population of UCP1-containing multilocular adipocytes
- Adipocytes with an intermediate morphology
- Areas between BAT and WAT [76]
- Varied morphology and degree of UCP1 expression in these adipocytes
- Some were UCP1-negative
- Others were UCP1-positive
- Brown marker UCP1
- UCP1 immunoreactivity is acquired only upon achievement of a given degree of mitochondrial differentiation [76]
- Direct, reversible transdifferentiation of white adipocytes into brown adipocytes
- Cold-induced UCP1-expressing adipocytes
- From posterior subcutaneous fat turned into unilocular adipocytes
- Not all white adipocytes seem to have the ability to turn into brown adipocytes
- Distance from noradrenergic fibres
- Positive correlation between the density of brown adipocytes and the density of noradrenergic fibres [76]
Charakteristika
- WAT contains small clusters of brown-like adipocytes that express UCP-1
- Multilocular
- Express
- UCP-1
- PGC1alpha (PPAR alpha Coactivator 1 alpha) [80]
- More frequently in certain anatomical locations
- Inguinal fat [80]
- Different embryonic precursors than brown adipocytes
- Gene signatures (Petrovic et al., 2010)
- CD137, TBX1, TMEM26 (Walden et al., 2012; Wu et al., 2012)
- Markers of “browning ”
- PRDM16
- PGC1 alpha
- Seem to come from different embryonic precursors than brown adipocytes
- Increase in activity are regulated different than brown adipocytes [80]
- CD137 as a marker of “browning” in human adipocytes (Elsen et al., 2014)
White adipose tissue
- Characteristic large lipid droplet
- Fills the cellular space
- Triacylglycerols constituting up to 85% of tissue weight
- Nuclei, mitochondria placed near the cellular membrane [80]
- Many depots all along the body
- Cca 10–15% of the total body weight
- Increases up to 50% in obese subjects [80]
- Organs as the kidney, heart and the gonads (perirenal or perigonadal depots) are also cover by fat
- Not pure WAT
- Some of them are located in the primitive BAT locations as found in hibernating animals [80]
Visceral fat Increase
- Is associated to
- Insulin resistance
- Metabolic syndrome
- Cardiovascular diseases [80]
Cells of WAT
- Considerable heterogeneity
- Mature adipocytes
- Tissue contains
- Fibroblasts
- Endothelial cells
- Preadipocytes
- Macrophages [78]
Markery pro WAT
- Tcf21 is present
- Transcription factor that inhibits myogenesis
Expressed in white adipocytes
- 14 members of the facilitative glucose transporter (GLUT) gene family (gene name SLC2A)
- GLUT1, GLUT3, GLUT4, GLUT5, GLUT8, GLUT10, GLUT12,
- HMIT ( Yao, Wood, and Trayhurn, unpublished observations) [78]
- Each with its own distinct kinetic characteristics
- At least one (GLUT4) displaying insulin sensitivity [78]
Sympatikus
- Lipolytic activity of adipocytes depends on
- Balance between
- Lipolysis-promoting beta-adrenergic receptor
- Lipolysis-inhibiting a2-adrenergic receptor
- Increased sympathetic tone can lead to an
- Increase or a decrease in lipolysis [78]
Parasympathetic innervation of WAT
- Vagotomy was shown to reduce the insulin-dependent glucose and free fatty acid uptakes
- Presence of functional nicotinic receptor on white adipocytes
- Increased insulin sensitivity of these cells under nicotine stimulation [78]
White adipose tissue
The apparent simplicity of both white adipocytes and of WAT itself, histologically and metabolically, is the key reason why the organ has been relatively ignored until recently. With triacylglycerols constituting up to 85% of tissue weight, it is not surprising that WAT was regarded as essentially limited in function to lipid synthesis and breakdown. The simplicity is, however, illusory. At the cellular level, there is considerable heterogeneity, with mature adipocytes accounting for no more than half of the total cell content of white fat, the tissue containing fibroblasts, endothelial cells, preadipocytes, and macrophages, for example (17–19). Complexity is also evident at the level of the basic process of glucose transport into white adipocytes; of the 14 members of the facilitative glucose transporter (GLUT) gene family (gene name SLC2A), as many as 8, GLUT1, GLUT3, GLUT4, GLUT5, GLUT8, GLUT10, GLUT12, and HMIT, are expressed in white adipocytes (20; Yao, Wood, and Trayhurn, unpublished observations). Thus, the process of sugar uptake into white adipocytes is thought to involve a range of different transport proteins, each with its own distinct kinetic characteristics, and at least one (GLUT4) displaying insulin sensitivity.
WAT is a major secretory organ, particularly through the release of fatty acids during fasting. The tissue also releases other lipid moieties, such as cholesterol, retinol, steroid hormones, and prostaglandins (21). Cholesterol and retinol are not synthesized by WAT, but rather are taken up and stored within the tissue. Steroid hormone conversions can take place in white adipocytes, such as the activation of 11-dehydrocorticosterone to corticosterone catalyzed by 11ß-hydroxysteroid dehydrogenase type 1 (22). The enzyme lipoprotein lipase is released from adipocytes for the breakdown of circulating triacylglycerols to fatty acids, which are subsequently stored within fat cells. In the late 1980s, a further secreted protein from adipocytes was identified, namely, adipsin, a complement-related factor (23,24). Adipsin was initially thought to be a direct signal in energy balance, but this was subsequently found not to be the case.
A major step forward in the recognition of the secretory role of WAT occurred in the early 1990s with the discovery that the proinflammatory cytokine tumor necrosis factor-? (TNF-?) is synthesized and released by adipocytes (25). TNF-? expression increases in obesity, and this cytokine plays an important role in the induction of insulin resistance (26,27). TNF-? was shown to have extensive metabolic effects in adipose tissue, including the stimulation of lipolysis and apoptosis (28,29).
The pivotal change in perspective on the role of WAT as a secretory organ came with the identification of the hormone leptin in 1994 (30). This followed the search for the Ob gene, a mutation in which is responsible for the obesity of the ob/ob mouse (30). Leptin, a 16,000 MW cytokine-like protein, is a critical hormonal signal from adipocytes in the regulation of appetite and energy balance (21,31,32), interacting with several hypothalamic orexigenic and anorexigenic pathways. Thus, the neuropeptide Y, melanin-concentrating hormone, orexin A, agouti-related peptide, and cannabinoid systems have each been reported to be inhibited by leptin (33–37). In contrast, the key anorexigenic systems of pro-opiomelanocortin/melanocortin, cocaine- and amphetamine-regulated transcript, and corticotrophin-releasing hormone are upregulated by the hormone (33,34,37,38). These multiple effects of leptin result in a powerful suppression of food intake.
In addition to inhibiting intake, leptin plays a role in the regulation of energy expenditure; a potent example of this comes from overfeeding studies on normal and ob/ob mice. In one study, lean mice fed a “cafeteria diet” overate by ~70% in energy terms with no additional energy deposition; this is a powerful illustration of the much debated phenomenon of diet-induced thermogenesis (39,40). Serendipitously, in this particular study, the energy intake of the lean mice fed the cafeteria diet was the same as that of ob/ob mice fed a standard laboratory diet. However, the rate of energy deposition of the obese was 3 times that of the lean (39). Thus, the ob/ob mutants lacking functional leptin had a greatly reduced capacity for diet-induced thermogenesis.[50]
Demonstrated that the lipolytic activity of adipocytes depends on a balance between lipolysis-promoting ß-adrenergic receptor and lipolysis-inhibiting a2-adrenergic receptor (10, 11). Depending on this balance an increased sympathetic tone can lead to an increase or a decrease in lipolysis. For a long time it was thought that white adipose tissues did not received parasympathetic nerves. Recent neuro-anatomical studies in rats have reported parasympathetic innervation of WAT. A physiological role of such input was proposed since vagotomy was shown to reduce the insulin-dependent glucose and free fatty acid uptakes (12). Such role of PNS can be also sustained by the demonstration of the presence of functional nicotinic receptor on white adipocytes as well as an increased insulin sensitivity of these cells under nicotine stimulation (13). However the PNS innervation of WAT remains a subject of debates (14, 15). [78]
Hnědá tuková tkáň - Brown adipose tissue (BAT)
- BAT function is the production of heat under cold exposure (facultative thermogenesis)
- By the mitochondrial uncoupling protein (UCP-1)
- After activation of the sympathetic nervous system (SNS), NE is released (Ricquier et al., 1986)
- NE binds to the adrenergic receptors
- Adenylyl cyclase is activated increasing cAMP levels
- Activates lipolysis
- Producing FFA which activate UCP1 (Cannon and Nedergaard, 2004)
- The amount of UCP-1 = index of the thermogenic capacity of BAT
- UCP-1 transcription
- Activated by NE or cold exposure (Bouillaud et al., 1984; Bianco et al., 1988)
- T3 increases the adrenergic stimulation of UCP1 (Obregon et al., 1987; Bianco et al., 1988, 1992; Giralt et al., 1990)
- In thermoneutral conditions and during the intrauterine life
- T3 is required for the expression of UCP1 mRNA
- Euthyroidism is required during the first postnatal days for the increases in UCP1 mRNA (Obregon et al., 1987)
- Increased ability to oxidize lipids
- Produce heat due to the
- High number of mitochondria
- Expression of the uncoupling protein-1 (UCP-1) [6]
- Activated:
- Low temperature conditions [6]
- Very sensitive to insulin
- Metabolically active BAT in adults
- Cervical regions
- Thoracic regions (Cypess, PET-18F-FDG and immunohistochemistry)
- Multilocular adipocytes
- Positive UCP-1 staining [6]
- BAT activity is correlated with
- Increased energy expenditure
- Weight loss
- fat mass loss [6]
- Obese individuals
- Decreased BAT activity [6]
- Burn glucose and lipids to maintain thermal homeostasis
- Cold exposure induces an increase in the 'brown' component
- In states of positive energy balance, the 'white' component expands to store excess nutrients
- Direct transdifferentiation of fully differentiated adipocytes
- By the stimuli that induce genetic expression reprogramming
- Change in phenotype and function
- Browning
- Pinking in breast cancer [23]
- +Uncoupling protein 1
- In the internal mitochondrial membrane
- Obesity reduction and insulin sensitization
- Achieved by BAT activation-regeneration in animal models
- Therapeutic strategies for the treatment of metabolic disorders related to obesity
- Combining
- Stem cells from the adipose tissue with active components
- melatonin [41]
- Non-shivering thermogenesis
- Depletion of excess calories [43]
- Facultative thermogenesis
- Accomplished by the uncoupling protein (UCP)
- Uncouples oxidative phosphorylation
- Tissue is under the control of the sympathetic nervous system
- Direct noradrenergic innervation of brown adipocytes
- norepinephrine (NE)
- Released from the sympathetic nerve endings
- Main mediator of the proliferative stimulus in BAT activation
- Adaptive or facultative thermogenesis
- Activated in response to
- Cold exposure
- fat diets [80]
- Providing extra heat in demanding situations to maintain energy balance
- Abundant in
- Small rodents
- Hibernating animals
- Newborns [80]
- In small pads in the
- Interscapular
- Cervical region [80]
- Protecting heart, aorta, kidneys
- And other organs that should be heated up during the arousal from hibernation [80]
- Main function of BAT is to produce heat
- Activation of the uncoupling protein 1 (UCP1)
- Producing heat, instead of ATP
- Switch on by the adrenergic stimulation [80]
- Highly innervated and irrigated tissue
- Characterized by multilocular lipid droplets
- Can be easily mobilized [80]
- Multiple and active mitochondria
- Number and activity increases under cold exposure (mitochondriogenesis) [80]
- Activation of BAT is considered as a possible therapeutic tool to fight obesity
- Brown adipocytes
- Have a myogenic origin
- Different from white adipocytes [80]
- Defined by the expression of the myogenic marker
- Myogenic factor 5
- Myf5+ also found in myoblasts [80]
- Markers of its terminal differentiation
- UCP1 and D2 [80]
- Multilocular
- Express
- UCP-1
- Cidea (Cell death activator CIDE-A)
- PGC1 (PPAR gamma Coactivator 1 alpha) [80]
- Adrenergic input
- Increases D2 deiodinase in BAT (Silva and Larsen, 1983)
- Increases in BAT T3
- T3 has an important role in thermogenesis
Hnědá tuková tkáň - Brown adipose tissue (BAT)
Facultative thermogenesis
- Production of heat under
- Cold exposure
- fat diets [80]
- By the mitochondrial uncoupling protein (UCP-1)
- After activation of the sympathetic nervous system (SNS)
- NE is released (Ricquier et al., 1986)
- Binds to the adrenergic receptors
- Adenylyl cyclase is activated increasing cAMP levels
- Activates lipolysis
- Producing FFA which activate UCP1 (Cannon and Nedergaard, 2004)
- Uncouples oxidative phosphorylation
- Producing heat, instead of ATP
Amount of UCP-1
- = index of the thermogenic capacity of BAT
- In the internal mitochondrial membrane
UCP-1 transcription
- Activated by NE or cold exposure (Bouillaud et al., 1984; Bianco et al., 1988)
UCP - 1 expression
- In thermoneutral conditions and during the intrauterine life
- T3 is required for the expression of UCP1 mRNA
- Euthyroidism is required during the first postnatal days for the increases in UCP1 mRNA (Obregon et al., 1987)
- Increased ability to oxidize lipids
- Produce heat due to the
- High number of mitochondria
- Expression of the uncoupling protein-1 (UCP-1) [6]
UCP - 1 Stimulation
- T3 increases the adrenergic stimulation of UCP1 (Obregon et al., 1987; Bianco et al., 1988, 1992; Giralt et al., 1990)
BAT activation
- Low temperature conditions [6]
- Cold exposure induces an increase in the 'brown' component
- Very sensitive to insulin
- Metabolically active BAT in adults
- Cervical regions
- Thoracic regions (Cypess, PET-18F-FDG and immunohistochemistry)
- Multilocular adipocytes
- Positive UCP-1 staining [6]
- Obesity reduction and insulin sensitization
- Achieved by BAT activation-regeneration in animal models
- Therapeutic strategies for the treatment of metabolic disorders related to obesity
- Combining
- Stem cells from the adipose tissue with active components
- melatonin [41]
- Considered as a possible therapeutic tool to fight obesity
BAT activity
- Correlated with
- Increased energy expenditure
- Weight loss
- fat mass loss [6]
- Burn glucose and lipids to maintain thermal homeostasis
- Non-shivering thermogenesis
- Depletion of excess calories [43]
BAT inhibition
- Obese individuals
- Decreased BAT activity [6]
- Low BAT function is associated to increases in body fat or insulin resistance
Transdifferentiation
- In states of positive energy balance, the 'white' component expands to store excess nutrients
- Direct transdifferentiation of fully differentiated adipocytes
- By the stimuli that induce genetic expression reprogramming
- Change in phenotype and function
- Browning
- Pinking in breast cancer [23]
Sympatikus
- Direct noradrenergic innervation of brown adipocytes
- norepinephrine (NE)
- Main mediator of the proliferative stimulus in BAT activation
- Adrenergic input
- Increases D2 deiodinase in BAT (Silva and Larsen, 1983)
- Increases in BAT T3
- T3 has an important role in thermogenesis
BAT lokalizace
- Abundant in
- Small rodents
- Hibernating animals
- Newborns [80]
- In small pads in the
- Interscapular
- Cervical region [80]
- Brown adipocytes were also found in WAT (Guerra et al., 1998; Xue et al., 2005, 2007)
BAT funkce
- Providing extra heat in demanding situations to maintain energy balance
- Protecting heart, aorta, kidneys
- And other organs that should be heated up during the arousal from hibernation [80]
- Main function of BAT is to produce heat
- Activation of the uncoupling protein 1 (UCP1)
BAT charakteristika
-highly innervated and irrigated tissue
- Characterized by multilocular lipid droplets
- Can be easily mobilized [80]
- Multiple and active mitochondria
- Number and activity increases under cold exposure (mitochondriogenesis) [80]
- Myogenic origin
- Different from white adipocytes [80]
- Defined by the expression of the myogenic marker
- Myogenic factor 5
- Myf5+ also found in myoblasts [80]
- Markers of its terminal differentiation
- UCP1 and D2 [80]
- Cidea (Cell death activator CIDE-A)
- PGC1 (PPAR gamma Coactivator 1 alpha) [80]
- Other markers
- PRDM16
- BMP7, BMP4
- Zic1
Browning of the fat tissue
- Irisine
Inducibility of BAT
- Human BAT may be largely composed of inducible 'beige' adipocytes
- More than typical brown adipocytes [12]
- Preadipocytes isolated from supraclavicular fat deposits
- Where BAT is often detected
- Capable of differentiating into brown-like adipocytes in vitro
- Inducible brown adipogenesis in adult humans [12]
Pink adipocyte
- In mouse subcutaneous fat depots during pregnancy and lactation
- Are mammary gland alveolar epithelial cells
- Produce and secrete milk
- Derive from the transdifferentiation of subcutaneous white adipocytes [23]