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1 Department of Endocrinology, Clínica Universitaria de Navarra, 2 Metabolic Research Laboratory, and 3 Department of Histology and Pathology, University of Navarra, 31008 Pamplona, Spain
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ABSTRACT |
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 TOP
 ABSTRACT
 OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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The ability to ensure
continous availability of energy despite highly variable supplies in
the environment is a major determinant of the survival of all species.
In higher organisms, including mammals, the capacity to efficiently
store excess energy as triglycerides in adipocytes, from which stored
energy could be rapidly released for use at other sites, was developed.
To orchestrate the processes of energy storage and release, highly
integrated systems operating on several physiological levels have
evolved. The adipocyte is no longer considered a passive bystander,
because fat cells actively secrete many members of the cytokine family,
such as leptin, tumor necrosis factor-
, and interleukin-6, among
other cytokine signals, which influence peripheral fuel storage,
mobilization, and combustion, as well as energy homeostasis. The
existence of a network of adipose tissue signaling pathways, arranged
in a hierarchical fashion, constitutes a metabolic repertoire that
enables the organism to adapt to a wide range of different metabolic
challenges, such as starvation, stress, infection, and short periods of
gross energy excess.
leptin; tumor necrosis factor-; interleukins; obesity; insulin
resistance
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OVERVIEW |
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TOP
ABSTRACT
OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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Unraveling the diverse hormonal and neuroendocrine systems that regulate energy balance and body fat has been a long-standing challenge in biology, with obesity as an increasingly important public health focus (12). Adipose tissue is the body's largest energy reservoir. For example, an adult with 15 kg of body fat has >460 MJ (110,000 kcal) of lipid fuel stores, which could provide 8.37 MJ (2,000 kcal) daily for ~2 mo (75, 129). The primary role of adipocytes is to store triacylglycerol during periods of caloric excess and to mobilize this reserve when expenditure exceeds intake. Mature adipocytes are uniquely equipped to perform these functions. They possess the full complement of enzymes and regulatory proteins needed to carry out both lipolysis and de novo lipogenesis. In fat cells, the regulation of these processes is exquisitely responsive to hormones, cytokines, and other factors that are involved in energy metabolism (87). The ability to carry out these functions is acquired during embryonic development in preparation for the postnatal period, when an adipose energy reserve becomes necessary. Major expansion of the white adipocyte population is delayed until shortly after birth, although preadipocytes first appear late in embryonic life (22).
The present review will focus on the evidence for the synthesis and secretion by white adipocytes of endocrine, paracrine, and autocrine signals implicated in energy balance regulation, with special reference to cytokines. The interactions between these adipose tissue-derived mediators and other neuroendocrine pathways will be examined. Furthermore, the metabolic alterations in adipose tissue signaling leading to obesity and insulin resistance will be described.
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WHITE ADIPOSE TISSUE SIGNALS |
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TOP
ABSTRACT
OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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Adipocytes, which vary enormously in size (20-200 µm in
diameter), are embedded in a connective tissue matrix and are uniquely adapted to store and release energy. Surplus energy is assimilated by
fat cells and stored as triglycerides in lipid droplets. To accommodate
the lipids, adipocytes are capable of changing their diameter 20-fold
and their volumes by several thousandfold. Because ~90% of the cell
volume is a lipid droplet, the nucleus and the thin cytoplasmic rim are
pushed to the periphery of the adipocytes. White adipose tissue is
actively involved in cell function regulation through a complex network
of endocrine, paracrine, and autocrine signals that influence the
response of many tissues, including hypothalamus, pancreas, liver,
skeletal muscle, kidneys, endothelium, and immune system, among others.
Until recently, the adipocyte has been considered to be only a passive
tissue for the storage of excess energy in the form of fat
(37). However, there is now compelling evidence that
adipocytes act as endocrine secretory cells (37, 143). It
has been shown that several hormones, growth factors, and cytokines are
actually expressed in white adipose tissue (Tables
1 and
2). In a dynamic view of the
adipocyte, a wide range of signals emanates from white adipose tissue,
such as leptin, tumor necrosis factor- (TNF-), interleukin-6
(IL-6), and their respective soluble receptors. White adipose tissue
also secretes important regulators of lipoprotein metabolism, like lipoprotein lipase (LPL), apolipoprotein E (apoE), and cholesteryl ester transfer protein (CETP). The increasing number of products secreted by adipocytes also includes angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), tissue factor, and transforming growth
factor-
(TGF-). Nitric oxide synthase (NOS) has also been
reported to be expressed in rat white adipose tissue, indicating that
adipocytes are a potential source of NO production (131). Recently, evidence for an involvement of NO in both rat and human lipolysis has been published (3, 48). Interestingly,
leptin immunolabeling of white adipocytes exhibits an absolutely
superimposable staining pattern to that of inducible NOS (iNOS), as can
be observed in histological sections (Fig.
1 and
2). The role of insulin-like growth
factor I (IGF-I), glucocorticoids, and sex steroids in adipose tissue
proliferation, heterogeneity, and distribution is beginning to be
better understood. However, the influence of acylation-stimulating
protein (ASP), adipophilin, adipoQ, adipsin, monobutyrin, agouti
protein, and factors related to proinflammatory and immune processes
still remains to be fully elucidated (14). These
relationships show that white adipose tissue lies at the heart of a
network of autocrine, paracrine, and endocrine signals (Fig.
3). Through the existence of a network of
local and systemic signals, which interact with neuroendocrine
regulators, adipose tissue signaling pathways, arranged in a
hierarchical fashion, constitute one of the voices of the body that
enable the organism to adapt to a range of different metabolic
challenges, such as starvation, stress, and infection, as well as
periods of gross energy excess.
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ADIPOCYTE SECRETORY PRODUCTS AND THEIR METABOLIC EFFECTS |
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TOP
ABSTRACT
OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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Adipocytes produce a great number of factors that serve as feedback signals to regulate adipose tisssue metabolism. Undoubtedly, the development of sophisticated molecular techniques has contributed to the identification of many of the secretory products of adipose tissue.
Adipsin
Adipsin is a serine protease secreted by fat cells. It was originally identified as a highly differentiation-dependent gene in 3T3-L1 adipocytes (21). Expression of adipsin is markedly downregulated in rodent obesities, probably as a consequence of increased concentrations of insulin and glucocorticoids (21). Sequence comparison revealed that both murine adipsin and human adipsin were identical to complement D (165), the initial and rate-limiting enzyme in the alternative complement pathway. It was shown that fat cells synthesize all of the proteins of the alternative complement pathway, namely factors C3, D (adipsin), and B (19). The proximal, nonlytic portion of the pathway is operative in adipose tissue, and, in vitro, the proteolytic cascade results in the production, among others, of biologically active C3a, Ba, and Bb (19). In cultured fat cell lines and other tissues, the activity of the alternative complement pathway requires stimulation by cytokines. However, the proximal pathway is fully functional in adipose tissue fragments, even without stimulation by cytokines, probably as a result of endogenous cytokine production. Further research is required to determine the primary functions and regulation of the alternative complement pathway in adipose tissue. The fact that partially acquired lipodystrophy is associated with constitutive activation of the alternative complement pathway points to a potential pathophysiological role of this pathway (19, 153).ASP
A 14-kDa serum protein resulting from the cleavage of the terminal arginine residue from C3a by plasma carboxypeptidases was named the acylation-stimulating protein (ASP) (41). Because C3a is the end product of the alternative complement pathway, of which factor D, adipsin, is a main component, it was proposed that it should be designated the "adipsin-ASP pathway" (148).Several roles for ASP in adipocyte metabolism have been proposed (41). It may be involved in the uptake and esterification of fatty acids to make triglycerides and facilitate fatty acid storage in the postprandial state. ASP increases after a fat-containing meal and stimulates triglyceride synthesis via diacylglycerol acyltransferase in adipocytes and fibroblasts. Although ASP is expressed by both preadipocytes and fibroblasts, ASP formation is, predominantly, a feature of mature and fully differentiated adipocytes (106). ASP stimulates triglyceride production to a greater extent than insulin, as well as having an additive effect with that of insulin (185). ASP also stimulates translocation of glucose transporters to the cell surface, probably by activation of the diacylglycerol-protein kinase C pathway (49). The fact that ASP is more potent in triglyceride synthesis stimulation supports a role for ASP in determining the rate at which fatty acids, derived from circulating triglycerides hydrolyzed by LPL, are esterified and stored in adipose tissue. Studies in ASP functional knockout mice support the putative role in triglyceride storage. Knockout mice have shown a delayed triglyceride clearance compared with wild-type animals, and this difference is further exaggerated in female mice. The delay in triglyceride clearance may be due to the effect on LPL of increased nonesterified fatty acid concentrations. Differences between adipose tissue depots have been detected, with greater degrees of ASP binding in subcutaneous compared with omental fat, in females compared with males, and in morbidly obese compared with nonobese individuals (111).
In contrast to rodent models, serum adipsin concentrations tend to be increased in obese human subjects, whereas adipsin secretion per adipocyte is normal (149). However, when we consider that adipsin production is not elevated in proportion to the increased fat cell size, in contrast to many other adipocyte proteins, the relatively lower ASP production could play a limiting role in the triglyceride synthesis rate as fat cells enlarge. Consistent with this reasoning, in vivo studies have shown that esterification of triglyceride fatty acids released by LPL is less efficient in obese than in lean subjects (39, 127). Further research will help to clarify whether the major role of ASP lies in regulating local triglyceride uptake by adipocytes, as well as whether adipose tissue contributes to the pool of serum ASP and thus to systemic triacylglycerol clearance. Furthermore, the exact nature of the participation of the adipsin-ASP pathway in fat cell size regulation, together with the concrete mechanism of action of ASP, still remains unknown.
Adipose Fatty Acid-Binding Protein
Fatty acid-binding proteins are abundant low-molecular-weight cytoplasmic proteins that are thought to be involved in the intracellular transport and metabolism of fatty acids (129). Different members of this gene family are expressed in a tissue-specific manner, with several tissues expressing more than one fatty acid- binding protein type. The adipose-specific fatty acid-binding protein, also known as aP2, is expressed during adipocyte differentiation and comprises up to 6% of cytosolic protein in the mature fat cell (152). Adipose fatty acid-binding protein has been shown to be involved in intracellular trafficking and targeting of fatty acids (183). This cytosolic adipose fatty acid-binding protein is postulated to shuttle fatty acids within the aqueous cytosol toward the membranes of the relevant intracellular organelles that are involved in triglyceride synthesis or fatty acid oxidation. This transfer is believed to occur via a collisional mechanism dependent on the interaction of organelle membrane phospholipids with the basic residues of aP2, resulting in partitioning of fatty acids to organelles for metabolic utilization (183). Knockout of aP2 (aP2
/) results in
increased expression of keratinocyte fatty acid-binding protein
(63). Under normal circumstances, the keratinocyte fatty acid-binding protein is principally expressed in skin and at low levels
in adipose tissue. aP2/ mice show few phenotypic
changes when fed a standard low-fat diet, with the exception of
slightly lower plasma glucose and triglyceride concentrations in the
fasted state (63). However, in contrast to wild-type
controls, high-fat feeding did not lead to hyperinsulinemia and
insulin resistance in aP2/ mice, despite similarly
elevated body weights. No major abnormalities in adipocyte triglyceride
synthesis or lipolysis were observed in aP2/ mice with
compensation by keratinocyte fatty acid-binding protein (144). Therefore, deficiency of aP2 was not associated
with protection from mild insulin resistance resulting from short-term
high-fat feeding. Thus, with the possible exception of de novo fatty
acid synthesis, keratinocyte fatty acid-binding proteins are capable of
adequately substituting for aP2. Consistent with these findings, adipose tissue expression of TNF- mRNA, a proposed mediator of insulin resistance, was reported to be increased in obese wild-type mice but not in aP2/ animals (63). These
observations point to the fact that fatty acid-binding proteins are
involved in mediating obesity-induced alterations in adipocyte gene
expression. Furthermore, because it is reasonable to think that fatty
acid-binding proteins may modulate lipolytic rate, and because
increases in fatty acid flux are thought to play a role in
obesity-induced insulin resistance, it was postulated that these would
cause an impairment in lipolysis (63).
Adipocyte Complement-Related Protein of 30 kDa
While a substraction cDNA library of mRNAs induced during differentiation of 3T3-L1 adipocytes was screened, an adipocyte complement-related protein of 30 kDa (Acrp30), another secretory protein belonging to the collectin family and expressed by fat cells, was found (67, 140). Acrp30, also called adipoQ, adiponectin, and adipose most abundant gene transcript 1 (apM1), is a relatively abundant serum protein that accounts for ~0.01% of the total plasmatic protein and shows similarity to complement factor C1q. Its expression is markedly reduced in adipose tissue of obese mice and humans (140). Its function is still unknown; however, like adipsin, its secretion is modulated by insulin, pointing to the possibility that its expression is regulated by the nutritional state. Adiponectin has been shown to suppress the attachment of monocytes to endothelial cells, which is an early event in atherosclerotic vascular change, thus suggesting a protective role against vascular damage. Furthermore, decreased plasma adiponectin concentrations may be an indicator of macroangiopathy in type 2 diabetic patients (66).Agouti Protein
The agouti gene encodes a secreted protein that acts in a paracrine manner to antagonize the melanocyte-stimulating hormone receptor, thereby regulating mouse coat color (102). Under normal circumstances, the agouti protein is expressed only in skin of mice. Dominant mutations in the agouti locus cause agouti to be expressed in all tissues, producing a syndrome consisting of yellow fur, obesity, hyperinsulinemia, and insulin resistance (86). Ectopic expression of agouti in transgenic mice reproduces this syndrome (86). In contrast to mice, the human agouti gene is normally expressed in adipose tissue and testis, suggesting a role for this protein in regulating adipose tissue function. The participation of the agouti protein in the development of insulin resistance has been proposed to be through increasing intracellular free calcium concentrations (191).Angiotensinogen
Angiotensinogen is primarily synthesized by the liver, although angiotensinogen mRNA is present in several tissues, including adipose tissue (76). Angiotensinogen is the substrate of renin in the renin-angiotensin system and is converted into angiotensin I, the precursor of angiotensin II. The physiological and pathological role of angiotensinogen gene expression in adipose tissue has not been completely elucidated. Angiotensin II has been suggested to influence adipocyte differentiation by interactions with angiotensin receptors, inducing fat cells to produce prostacyclin (24). Angiotensinogen expression is increased in obesity and, in contrast to the hepatic expression, is regulated by the nutritional status (41). During fasting, a decrease in mRNA above control has been observed, which increases upon refeeding. Furthermore, these changes in gene expression are paralleled by fluctuations in angiotensinogen secretion from isolated adipocytes. Angiotensinogen mRNA in both subcutaneous and omental fat correlates with the waist-to-hip ratio, with higher mRNA expression in the omental than in the subcutaneous adipose depot (171). Angiotensinogen may play a role in local adipose tissue blood flow and, hence, in rates of fatty acid reesterification (171). Thus, by affecting both substrate availability and preadipocyte differentiation, angiotensinogen is able to regulate adipose size in response to nutritional signals.PAI-1
PAI-1 is a member of the family of serine protease inhibitors or serpins. By inhibiting the tissue plasminogen activator, it is the main regulator of the endogenous fibrinolytic system (182). Therefore, increased concentrations of PAI-1 favor the development of thromboembolic complications. Among the multiple mechanisms that may explain the relationship between obesity and cardiovascular disease, disorders of the fibrinolytic system seem to play a key role (78). Elevated plasma concentrations of PAI-1 have been found in obese subjects. A close correlation with an abdominal pattern of adipose tissue distribution in both men and women, as well as a positive association with other components of the insulin resistance syndrome, have been reported (78, 146, 170). The mechanisms responsible for the increase in PAI-1 are not yet completely established. Expression and secretion of PAI-1 in adipose tissue from humans and rodents have been demonstrated. However, little is known about its regulation at the adipocyte level. Insulin and TGF- appear
to be the main inducers of PAI-1 synthesis in adipose tissue
(136). TNF-, as well as IL-1, also has a stimulatory
effect on PAI-1 protein secretion and may contribute to the augmented
PAI-1 concentrations observed in obesity and insulin resistance
(9). Insulin has been reported to elevate PAI-1 production
in cultured hepatocytes, suggesting that increased hepatic synthesis of
PAI-1 might account for its elevation in obese subjects
(41). Recently, however, elevated PAI-1 concentrations associated with obesity have been shown to result in part from insulin-mediated induction of PAI-1, specifically by adipocytes within
the fat itself (9). It has been shown that, in dieting obese women, the decrease in PAI-1 during weight loss is more closely
related to changes in fat mass than to changes in metabolic variables,
suggesting a significant role of adipose tissue in regulating plasma
PAI-1 concentrations (107). However, a strong correlation
exists between PAI-1 antigen and circulating leptin concentrations
irrespective of body mass index, and body fat mass seems to indicate
that leptin per se may potentially increase PAI-1 in obese subjects
(25, 150).
TGF-
is a multifunctional cytokine produced by a variety of
cells that is capable of regulating the growth and differentiation of
numerous cell types (137, 154). It has been implicated in a number of biological processes, including cell adhesion and migration, extracellular matrix production, tissue remodeling, and
wound repair.
TGF- mRNA expression has been shown to be higher in adipose tissue
of ob/ob and db/db mice compared with their lean
littermates (137). Moreover, this increase was due to
elevated expression of TGF- mRNA by mature adipocytes and cells of
the stromal/vascular fraction. TNF- contributes to the augmented
expression of TGF- in adipose tissue of obese mice. In this sense,
chronically elevated TNF- concentrations in adipose tissue of obese
individuals may act in an autocrine/paracrine manner and contribute to
increased TGF- expression in obesity. The elevated gene expression
of TGF- in adipose tissue may have broad implications in the
pathophysiology of obesity and its associated complications. TGF-
has been shown to increase preadipocyte cell proliferation. Thus the
augmented expression of TGF- in the obese adipose tissue may
increase adipocyte precursor cell proliferation, thereby contributing
to the elevated cellularity of fat depots related to the obese
phenotype. Both obesity and type 2 diabetes are also associated with
characteristic long-term complications, including microvascular kidney
disease. Interestingly, overexpression of TGF- in glomeruli has been
reported (41).
As mentioned before, TGF- stimulates PAI-1 biosynthesis in a variety
of cells, including adipocytes. Insulin failed to raise TGF- mRNA
expression in lean mice, even though significantly increasing the
expression of PAI-1 mRNA in adipose tissue (137). Administration of TGF- to lean mice has been shown to cause a 60-fold increase in plasmatic active PAI-1 and increased PAI-1 mRNA in
adipose tissue (137). The TGF--mediated induction of PAI-1 in 3T3-L1 adipocytes was considerably higher than the response of
these cells to TNF- and insulin. Similarly, the greatest PAI-1 response in adipose tissue in in vivo studies was to TGF- (36-fold), followed by TNF- (9-fold), and insulin (7-fold) (136,
137).
Growth Hormone
Growth hormone (GH) is an important regulator of body mass throughout life (4, 14). It has been observed that GH deficiency in both children and adults is characterized by abnormal body composition, with increased fat mass and decreased lean muscle mass. GH-deficient subjects exhibit increased visceral and subcutaneous adipose tissue depots, which are partly normalized by GH therapy (2, 4). Whereas subcutaneous adipose tissue decreased by an average of 13%, visceral fat depots were reduced by 30%. In contrast, in patients with acromegaly, a reduced fat mass was observed to return to normal after treatment of the hormone excess by octreotide or pituitary surgery. Adipocytes have specific GH receptors, with the hormone exerting a variety of direct metabolic effects, such as inhibition of glucose uptake and stimulation of lipolysis, which may cause a net loss of stored lipids (2).Sex Steroids
Two enzymes of relevance to sex steroid metabolism are present in adipose tissue, 17-hydroxysteroid oxidoreductase and
cytochrome-P-450-dependent aromatase (111).
Androstenedione, synthesized in the adrenal cortex, is converted by
17-hydroxysteroid oxidoreductase to testosterone. This same enzyme
converts estrogen and estrone to estradiol. Aromatization of androgens
to estrogens also takes place in white adipose tissue. The presence of
estrogens in the plasma of postmenopausal women led to the discovery
that adipose tissue was an active extraglandular producer of certain
steroid hormones (87, 111). Circulating C19 precursors of
adrenal origin are converted to estrone and estradiol via adipose
tissue P-450 aromatase (111). A net release of
testosterone, estradiol, and estrone from abdominal subcutaneous adipose tissue in women, but not in men, has been shown in
arteriovenous studies (132). A clear sexual dimorphism in
relation to the influence of sex steroids on adipose tissue function
has been observed.
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ADIPOCYTES AS A SOURCE OF CYTOKINES |
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TOP
ABSTRACT
OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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Cytokines are defined as soluble proteins synthesized by immune or
nonimmune cells, which mediate intercellular communication by
transmitting information to target cells through receptor-ligand interactions. This class of mediators is represented by cytolytic, chemotactic, and immunoenhancing growth and differentiation factors. Many cytokines have physiological activities far beyond those originally discovered. A prominent role for cytokines in the regulation of energy balance has evolved from recent investigations.
Proinflammatory cytokines with potent actions in host defense, like
TNF- and IL-6, have also important effects on both lipid and glucose
metabolism (53, 111).
IL-6
The term interleukin originally described a leukocyte-derived protein with activity for other leukocytes. It is now understood that both immune and nonimmune cells synthesize interleukins and other cytokines, which have diverse biological activities.Interleukin-6 expression in adipose tissue. Interestingly, production of IL-6, as well as systemic concentrations, has been shown to be positively correlated with body mass index (175). As much as a third of total circulating concentrations of IL-6 has been estimated to originate from adipose tissue (110, 184). In this sense, IL-6 may be both an autocrine and a paracrine regulator of adipocyte function. Omental fat produces threefold more IL-6 than subcutaneous adipose tissue, and adipocytes isolated from the omental depot also secrete more IL-6 than fat cells from the subcutaneous depot (40). Although it has now been clearly established that adipocytes themselves secrete IL-6 on a per lipid weight or per fat cell basis, this cell type accounts for only 10% of the total adipose tissue production, as evidenced by determination of IL-6 released by intact adipose tissue fragments and isolated adipocytes prepared from omental and subcutaneous fat depots (40). Thus other cells within the adipose tissue also contribute to the high release of IL-6. This is not surprising, because IL-6 is a multifunctional cytokine produced by many different cell types, including immune cells, fibroblasts, stromal-vascular cells, endothelial cells, myocytes, and a variety of endocrine cells (172). The amount of IL-6 produced by adipose tissue is similar to or greater than that reported for a variety of other tissues and cells, with the concentrations of IL-6 accumulating in adipose tissue or cell incubations (up to 75 ng/ml) being well within the range to elicit biological effects (51). Regardless of the cellular source of IL-6, it is interesting to note that adipose tissue may be an important source for the increased serum concentrations of IL-6 observed in obesity, with depot-specific differences in terms of both quantitative contribution to the serum pool and qualitative participation in lipid metabolism. Because the venous drainage from omental adipose tissue flows directly into the liver, the metabolic impact of IL-6 release from this fat depot may be of particular importance. In this sense, it has been shown that IL-6 increases hepatic triglyceride secretion (116) and may, therefore, contribute to the hypertriglyceridemia associated with visceral obesity.
IL-6 is secreted by adipose tissue under basal conditions. It has been shown that TNF- produces a 60-fold increase in IL-6 production in
differentiated 3T3-L1 adipocytes (53). Thus it is feasible
that adipose tissue TNF-, whose expression is elevated in obesity,
induces adipocyte and nonadipocyte IL-6 expression. Other important
modulators of IL-6 expression in different fat depots are
glucocorticoids and catecholamines (40, 119).
Dexamethasone markedly suppresses IL-6 production, whereas insulin has
no effect, suggesting that cortisol may act physiologically in the
modulation of IL-6 production. In primary cultures of murine
adipocytes, norepinephrine, isoprenaline, and a
3-selective agonist have been shown to stimulate IL-6
gene expression and protein secretion, whereas activation of
-adrenergic receptors had no effect (111).
IL-6 receptors. Class I cytokine receptors are known to act through Janus kinases (JAK) and signal transducers and activators of transcription (STAT). JAK proteins are associated with membrane-proximal sequences of the receptor intracellular domain, which is phosphorylated upon ligand binding. The phosphorylated intracellular domain then provides a binding site for a STAT protein, which is activated, translocates to the nucleus, and stimulates transcription. The biological activities of IL-6 are initiated by binding to a high-affinity receptor complex consisting of two membrane glycoproteins (160). The IL-6 receptor (IL-6R), the 80-kDa ligand-binding component, binds IL-6 with low affinity, but the 130-kDa signal-transducing component, gp130, although not binding free IL-6, is required for high-affinity binding of gp80-bound IL-6. It has been reported that IL-6-type cytokines use tyrosine kinases of the JAK family for signal transduction (71). Dimerization of the intracellular domains of two gp130 molecules brings the receptor-associated JAKs (JAK1, JAK2, and Tyk2) into close proximity, leading to activation via inter- or intramolecular phosphorylation and activation. Specific STAT proteins are recruited to the stimulated receptor complexes and are activated by direct phosphorylation by receptor-asscociated JAKs. The leukemia inhibitory factor (LIF), a member of the IL-6 family of cytokines, has been shown to activate the JAK/STAT pathway (71). After the activation of the signal transduction receptor gp130, LIF induces a rapid tyrosine phosphorylation of JAK1, JAK2, Tyk2, STAT1, and STAT3.
A soluble form of IL-6R (IL-6Rs), apparently arising from proteolytic cleavage of the membrane-bound receptor and with a molecular mass of ~50 kDa, has been found (157). The recombinant IL-6Rs has been shown to increase the activity of IL-6 as a result of the binding of the IL-6/IL-6Rs complex to the membrane-bound gp130 (160). Elevated concentrations of IL-6 have been suggested to be associated with increased production of IL-6Rs (133). Recently, evidence for a soluble form of the gp130 receptor, which may exert antagonist properties, has also been reported (186). In humans, subcutaneous adipose tissue has been shown to release IL-6 but not soluble receptors (109, 110). Therefore, a regulatory role for adipocytes in the bioavailability of cytokines has been put forward (111). However, neither the functional significance nor the regulation of soluble receptors is clearly understood.Biological effects of IL-6.
IL-6 decreases adipose tissue LPL activity and has been implicated in
the fat depletion taking place during cancer cachexia and other wasting
disorders (51, 158). Like TNF-, IL-6 has potent effects
on adipose tissue, as evidenced by the fact that neutralization of this
cytokine decreases the loss of adipose tissue during cachexia
(158). It seems unlikely that this effect is mediated
solely by the documented ability of IL-6 to downregulate LPL activity,
implying that IL-6 exerts other actions on adipocyte metabolism. IL-6
is considered to be an inflammatory mediator as well as a
stress-induced cytokine (189). It has pleiotropic effects
on a variety of tissues, including downregulation of adipocyte LPL,
stimulation of acute-phase protein synthesis, increase in the activity
of the hypothalamic-pituitary axis (HPA), and thermogenesis, consistent
with the candidate role of corticotropin-releasing hormone (CRH) as a
common mediator of both of these actions.
TNF-
is a cytokine, first identified as a macrophage product
implicated in the metabolic disturbances of chronic inflammation and
malignancy. The biological actions of TNF- include induction of
insulin resistance, anorexia, and weight loss. Since the discovery that
TNF- is involved in the loss of body fat in the course of wasting
disorders, a large number of studies investigated the physiological
role of this cytokine in adipose tissue (65, 81, 165).
TNF- expression in adipose tissue.
Hotamisligil et al. (65) were the first to describe
adipose expression of TNF- mRNA in different rodent models of
obesity. Clinical studies have also revealed expression of TNF mRNA in human adipose tissue (62, 68, 81). Subcutaneous fat depots exhibit a 1.67-fold higher TNF- mRNA expression than omental fat
depots (68). The amount of TNF- mRNA is positively
correlated with body adiposity and decreases in obese subjects after
weight loss (112). TNF- mRNA expression is also closely
correlated with hyperinsulinemia, showing positive associations with
fasting insulin and triglyceride concentrations (62).
takes place already in adipocyte precursor cells,
although the amount of specific mRNA increases only moderately in a
differentiation-dependent manner (69, 70). Interestingly,
compounds that are used for the induction of adipose differentiation,
such as the nonselective phosphodiesterase inhibitor IBMX and the
thiazolidinediones, are inhibitors of TNF- expression. In this
sense, it is tempting to speculate that the adipogenic effect of these
compounds may be at least partially mediated by a suppression of
endogenous TNF- production. Triglycerides and free fatty acids play
an important role as physiological inducers of TNF- expression.
Feeding high-fat diets (45% of the energy content) is followed by a
significant increase of TNF- mRNA in fat pads of rats
(113). Moreover, mice lacking the adipocyte fatty
acid-binding protein aP2 do not express TNF- in white adipose tissue
(63), indicating that fatty acids are critically involved in the regulation of TNF- expression in adipose tissue.
Expression pattern of TNF- receptors.
In addition to measuring TNF- mRNA, it is also important to study
the expression pattern of TNF receptors (TNFR) in adipose tissue.
TNF- interacts with two cell-surface receptors, p55 (p60 in humans)
and p75 (p80 in humans) (52). Regulation of the expression of these two receptors seems to underlie separate mechanisms, because
they present different cellular and tissue distribution patterns. The
p60 TNFR appears to be primarily involved in insulin receptor signaling
and glucose transport (121), and the p80 TNFR has been
shown to be involved in the pathogenesis of TNF-induced insulin
resistance (61, 96). The lack of p75 TNFR in diet-induced obese mice leads to body weight loss with improved insulin
concentrations and sensitivity (142). Obese mice deficient
in p55 TNFR showed slightly elevated insulin concentrations after 3 mo
of a high-fat diet, whereas mice lacking both receptors were
significantly hyperinsulinemic during the 4 mo of high-fat feeding
(142). The researchers concluded that TNFR may be required
for glucose homeostasis but do not exert a critical role in the
development of insulin resistance. Conversely, the lack of p55 TNFR in
ob/ob mice has been shown to cause an improvement of insulin
sensitivity, whereas a lack of the p75 TNFR alone did not alter insulin
action but potentiated the effect of p55 TNFR deficiency in animals
deficient in both receptors (168). Subsequent studies
performed in preadipocyte cell lines from these knockout mice confirmed
that TNF-induced insulin resistance, as well as alterations in the
adipogenic program, can be attributed predominantly to the actions of
the p55 TNFR (69).
and TNFR concentrations
provides additional information regarding the role of the TNF system in
human obesity. In contrast to the findings made in rodent models of
obesity, where a marked increase in circulating TNF- concentrations
has been found (65), in obese diabetic and nondiabetic patients, TNF- concentrations are not substantially elevated (55, 123). The expression of TNF- in human white
adipose tissue is relatively low. Thus it remains doubtful whether
adipose tissue is a major source of circulating TNF-
(68). This reasoning is also supported by an in vivo study
measuring arteriovenous differences across a subcutaneous adipose
tissue bed, which evidenced a nonsignificant contribution of white
adipose tissue to the serum concentrations of TNF-
(110).
Disagreements regarding the serum concentrations of the proteolytically
cleaved soluble TNFR in obese and insulin-resistant patients have also
been obtained. Some researchers have shown 30-40% higher
circulating concentrations of both soluble receptor subtypes in obese
compared with lean individuals (55), whereas another group
has found sixfold concentrations of the soluble p80 TNFR in obese
compared with lean subjects, but no differences in the circulating
concentrations of the soluble p60 TNFR (61). The
physiological relevance of these findings remains unknown. Both soluble
receptor subtypes bind to TNF- in vitro and inhibit its biological
activity by competing with cell-surface receptors for TNF-.
Therefore, the release of soluble receptors may represent a mechanism
of binding and inhibiting the TNF- not immediately bound to surface
receptors, thereby protecting other target cells and circumscribing its
effect (173). It is conceivable that soluble receptors
serve to neutralize circulating TNF-. The release of soluble
receptors may imply a desensitizing mechanism of cells to the effects
of TNF-. Conversely, low TNF- concentrations, binding to soluble
receptors, have been reported to stabilize TNF- and increase its
activity (69). Thus augmented concentrations of the
soluble receptors may reflect either a state of receptor inactivation
or an upregulated TNF system in obesity.
Biological effects of TNF-.
TNF- has pronounced catabolic effects in adipose tissue
(69). It suppresses LPL at the mRNA and protein levels, as
reported in many in vivo and in vitro studies. TNF- inhibits the
expression of the two master regulators of adipose differentiation, the
transcription factor CCAAT/enhancer binding protein- (CEBP) and
the nuclear receptor peroxisome proliferator-activated receptor-
2
(PPAR2) (156, 184). This suppression may result in the
subsequent downregulation of many adipocyte-specific proteins, such as
LPL, aP2, fatty acid synthetase, acetyl-CoA carboxylase,
glycerol-3-phosphate dehydrogenase (GPDH), and GLUT-4 among
others. Furthermore, mature adipocytes are stimulated to mobilize
lipids upon TNF- exposure, possibly via hormone-sensitive lipase
activation (56). Among the multiple properties of TNF-,
the antiadipogenic effect is especially relevant, because adipose
conversion of fat cell precursors is potently inhibited by TNF-
(122). Moreover, chronic treatment of mature fat cells
with TNF- has been shown to lead to a reversion of the adipocyte
phenotype back to a fibroblast-like morphology (122).
selectively mediates
apoptosis in tumor cells, it has been suggested that this could
also be of relevance for human preadipocytes and adipocytes (128). Programmed cell death could represent another
mechanism by which TNF- can modulate adipose tissue cellularity.
Thus TNF- could decrease adipose tissue mass by reducing not only
fat cell volume but also adipocyte number.
Adipose tissue expansion may occur by adipocyte hypertrophy,
hyperplasia, or both (14, 60). Fat cells reaching a
critical size trigger the events that result in proliferation of
adipocytes. An increase in fat cell size before the onset of adipocyte
hyperplasia has been observed in diet-induced obese rats
(47). Adipose tissue levels of TNF- and IGF-I have been
shown to be higher in both human and rodent obesity (45, 87,
105), but these paracrine factors have seemingly opposing
effects on adipose tissue development. IGF-I induces both mitogenic and
differentiation responses in preadipocyte cultures
(178), whereas TNF- inhibits the expression of
adipogenic enzymes (184). It can be hypothesized that
TNF- may exert a permissive role in adipose tissue expansion,
whereby its production increases when existing fat cells reach a
critical size. Because TNF- is a very potent inhibitor of
differentiation, it may act to drive cells into a mitogenic program
directly or by other mechanisms such as increasing growth factor
responsiveness. Recently, it has been shown that IGF-I, produced in
response to enlarging fat cells, acts synergistically with TNF- to
further enhance proliferation (89). The net result from
this interaction would be an increase of the stromal-vascular or
uncommitted cell pool whereby these cells might then be recruited to
become adipocytes or might alternatively serve as infrastructure to
support adipose tissue growth. Furthermore, it has been suggested that
loss of the ability of IGF-I to activate Shc signaling to
mitogen-activated protein kinase (MAPK) may be an early component of
adipogenesis (13).
Leptin
A major development in energy balance regulation has come with the discovery in 1994 of leptin, the protein product of the ob gene (196). The initial concept was that leptin informs the brain about the abundance of body fat, thereby allowing feeding behavior, metabolism, and endocrine physiology to be coupled to the nutritional state of the organism (1, 44). Leptin consists of four antiparallel-helices, connected by two long crossover links
and one short loop, arranged in a left-hand twisted helical bundle. The
interhelical angles and features of the long crossover loops are
similar to those found in the long-chain helical cytokine crystal
structures, which include granulocyte colony-stimulating factor (GSCF),
LIF, ciliary neurotropic factor (CNTF), and human GH (101,
193).
Leptin expression in adipose tissue. Leptin biosynthesis and release are governed by paracrine, endocrine, and neuroendocrine signals that impinge on the adipocyte (1, 44, 111, 166). Because leptin is secreted by fat cells in proportion to body fat stores, it has the potential to play a key regulatory role in fuel homeostasis (166). As would be predicted of a factor involved in energy balance, expression of the ob gene is subject to nutritional regulation. Fasting induces a fall in the level of ob mRNA, which is rapidly reversed on refeeding, and circulating leptin levels change in parallel with tissue mRNA (44, 166). Glucosamine infusion increases leptin expression in adipose tissue and induces de novo leptin synthesis in rat skeletal muscle (179). Glucose infusion and lipid infusion have similar effects on leptin expression in adipose tissue and muscle, raising the possibility that leptin acts as a sensor of nutrient flux in these tissues.
Evidence for a direct autocrine/paracrine effect of leptin on the lipolytic activity of isolated adipocytes has recently been reported (43). In addition, leptin has been shown to repress acetyl-CoA carboxylase gene expression, fatty acid synthesis, and lipid synthesis; these are biochemical reactions that contribute to lipid accumulation without the participation of centrally mediated pathways (145, 180, 181). Thus leptin is involved in the direct regulation of adipose tissue metabolism by both inhibiting lipogenesis and stimulating lipolysis (44). Insulin stimulates ob gene expression, as do estrogens and glucocorticoids, with the effects of the latter being maintained during chronic treatment. Although plasma leptin, thyroid-stimulating hormone (TSH), and adiposity correlate in euthyroid patients, there are conflicting reports on the effect of hypo- and hyperthyroidism on ob gene expression (1). Androgens and GH decrease ob gene expression (1, 6, 44). Similarly, cold exposure induces a sympathetically mediated suppression of the ob gene, leading to a rapid decrease in both ob mRNA and serum leptin concentrations (166). Plasma leptin concentrations and adipocyte ob mRNA expression are strongly correlated with estimates of obesity, and total fat mass, percent body fat, and body mass index are the best predictors (1). Leptin mRNA shows higher expression in subcutaneous than in omental adipocytes (112). In addition, a striking sexual dimorphism is evident in both ob mRNA expression and circulating leptin concentrations, with almost twofold higher leptin concentrations in women (44). Adipocyte size is an important determinant of leptin synthesis, because larger fat cells contain more leptin than smaller adipocytes from the same individual (1, 23). However, it is not known whether increased triglyceride contents, lipid metabolites, or mechanical factors associated with augmented adipocyte size influence leptin expression. It has been shown that a proportional increase in adipocyte size is insufficient to explain the sex- and site-specific differences observed (112). Omental fat depots represent a more rapidly mobilizable source of energy in the form of free fatty acids, particularly in response to stress hormones. Thus the observation of increased leptin mRNA in subcutaneous compared with omental adipocytes may imply that omental adipose tissue is a less important contributor to the long-term feedback loop controlling appetite and metabolic rate than subcutaneous adipose tissue. Although this property of omental fat may be advantageous in allowing a more efficient use of available calories in times of alternating food scarcity and plenty, in modern sedentary humans with an ensured food supply, reduced leptin mRNA expression, and hence leptin production from omental adipocytes, may contribute to the high prevalence of central obesity with its associated pathological consequences. Some researchers attribute the observed gender differences to the stimulating role of estrogens and the suppressive effect of circulating androgens, but other investigators have not been able to ascribe the sexual dimorphism to sex hormones (44, 103). Further studies will be required to address the molecular basis for and physiological consequences of depot- and sex-specific variation in ob mRNA expression in humans. Cell-autonomous factors such as intracellular metabolites, signaling molecules, or transcription factors act as other major links between adipocyte size and leptin gene expression (151). Like many other adipocyte genes, the ob gene promoter is positively regulated through a functional binding site for CEBP
(6). In contrast, thiazoladinedione agonists for PPAR
transcription factors suppress leptin expression (26).
This may partly involve a functional antagonism between CEBP and
PPAR on the leptin promoter, and this mechanism may explain the
downregulation of leptin expression by thiazoladinediones (1,
6).
Furthermore, leptin production is influenced by immune activation. In
this context, a positive and independent association between TNF-
and circulating leptin concentrations has been reported (104).
Leptin receptors. Consistent with leptin's pleiotropic effects, leptin receptors (OB-R) exhibit an almost universal distribution. The OB-R belong to the class I cytokine receptor family, which includes the receptors of IL-6, LIF, GSCF, and gp130 (1, 161). OB-R are produced in several alternatively spliced forms, designated OB-Ra, OB-Rb, OB-Rc, OB-Rd, and OB-Re. The receptors share an identical extracellular ligand-binding domain of 840 amino acids at the amino terminus, as well as a transmembrane domain of 34 amino acids, but they differ at the carboxy terminus. A variable intracellular domain, characteristic for each of the five receptor isoforms, has been identified. Only the full-length isoform, the OB-Rb, is believed to be involved in leptin signaling and is considered to be the functional receptor. Recent reports have shown that activation of OB-Rb, and to a lesser extent OB-Ra, mediates ligand-induced activation of both JAK and STAT proteins (1, 8). The extracellular and cytoplasmic regions of OB-R and gp130 possess conserved motifs and are closely related to each other. OB-R and gp130 appear to mediate overlapping but distinct cytoplasmic signals (114). Furthermore, recent reports have shown that OB-R stimulate transcription via IL-6 and hematopoietin receptor-responsive elements (8). Thus OB-R share, at least in part, some of the signaling pathways characteristic of the class I cytokine receptor family. The lack of the full-length OB-R has been shown to be responsible for the db/db mouse obesity phenotype and the fatty mutation (8, 161).
The OB-Re, which lacks the intracellular and transmembrane domains, circulates as a soluble receptor (93). Secreted extracellular domains of cytokine receptors are known to function as specific binding proteins (58). In mice, it has been observed that the putative soluble isoform, OB-Re, is produced at a level that is sufficiently high to act as a buffering system for free circulating leptin (97).Biological effects of leptin. Leptin has diverse effects in addition to appetite and body weight regulation. Many cytokines, originally isolated on the basis of particular biological actions, have subsequently been shown to be capable of stimulating a variety of biological responses in a wide spectrum of cell types. Thus leptin shares with other cytokines an extreme functional pleiotropy and has been shown to be involved in quite diverse physiological functions, such as reproduction (17), hematopoiesis (20), angiogenesis (147), immune responsiveness (98), blood pressure control (42), and bone formation (30).
It has been shown that leptin is necessary for maturation of the reproductive axis, as evidenced by its ability to restore puberty and fertility in ob/ob mice, accelerate puberty in wild-type mice, and facilitate reproductive behavior in rodents (1). Therefore, leptin signals the adequacy of energy stores for reproduction by interacting with different target organs in the hypothalamic-pituitary-gonadal axis (44). The functional OB-R has been shown to be capable of signaling for cell survival, proliferation, and differentiation into macrophages (20, 46). In addition, leptin appears to be able to enhance the production of cytokines in macrophages and to increase the attachment and subsequent receptor-mediated process of phagocytosis (46). This activity may be mediated by an upregulation of macrophage receptors or by increased phagocytic activity. In this sense, a role for leukocyte adhesion receptors in maintenance of normal body weight and adiposity has recently been described (28). In addition, leptin has a direct proliferative effect on T cells, showing an adaptive response of this hormone to enhance the immune competence of the organism against the immunosuppression associated with starvation (98). Leptin has to be included in the list of angiogenic factors secreted by adipose tissue, because it has been shown to cause cultured endothelial cells to aggregate, form tubes, and display a reticular array reminiscent of tissue vasculature (147). It has also been observed that leptin accelerates wound healing, a process depending on blood vessel growth. Regarding blood pressure homeostasis, leptin appears to have a balanced effect, with a pressor response attributable to sympathetic activation and a depressor response attributable to NO release (42). Therefore, leptin is involved in the control of vascular tone by simultaneously producing a neurogenic pressor action and an opposing NO-mediated depressor effect. In this sense, leptin may be one of the factors underlying the association of obesity with increased incidence of hypertension and cardiovascular mortality. A recent study identified leptin as a potent inhibitor of bone formation, acting through the central nervous system (30). Despite suffering from hypogonadism and hypercortisolism, known inducers of increased osteoclast number and bone resorption activity, leptin-deficient and OB-R-deficient mice exhibit a high bone mass phenotype. Interestingly, this phenotype is not secondary to obesity but is directly related to the lack of leptin signaling. Intracerebroventricular infusion of leptin to ob/ob and wild-type mice was followed by a significant bone mass reduction (30).| |
CROSS TALK AMONG ADIPOCYTE-DERIVED CYTOKINES |
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TOP
ABSTRACT
OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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TNF-, IL-6, and leptin share both structural and functional
similarities with other cytokines, including receptor homology, signaling via the JAK/STAT system, growth factor properties, and circulation in plasma, either in the free form or bound to specific serum proteins (7, 8, 44, 101, 161, 193). All three cytokines are expressed and released by adipocytes, exerting a key role
in fat mass control. TNF- induces the release of both IL-6 and
leptin from adipose tissue (54, 138). Knockout mice for
the TNF- gene showed a hypoleptinemia compared with wild-type mice
(85). Apparently, TNF- induces leptin production
through the p55 TNF receptor (36). All three cytokines,
TNF-, IL-6, and leptin, are closely interrelated as well as
influencing and being regulated by other hormones and the sympathetic
nervous system (Fig. 4) (111, 124,
194).
|
Proinflammatory cytokines have been shown to play a major role in the
initiation of the sepsis syndrome, with the amount and speed of their
release correlating with the occurrence of septic shock and,
eventually, with mortality (16). However, TNF- and IL-1
are seldom found in the circulation of septic patients. It has been
proposed that enhanced production of endogenous inhibitors of these
cytokines, such as soluble TNFR and IL-1 receptor antagonist, as well
as increased secretion of the anti-inflammatory cytokine IL-10, may be
important host defense mechanisms to attenuate concurrent proinflammatory cytokine activity during sepsis. Leptin synthesis is
stimulated by infection, endotoxin, and cytokines such as TNF-, LIF,
and IL-1 (54, 74, 138). The rise in leptin concentrations as a result of cytokine increase may contribute to the anorexia and
weight loss accompanying these inflammatory conditions. An independent
association for leptin with IL-1 receptor antagonist and IL-10 in
sepsis and septic shock has been described (5). In
addition, leptin and IL-6 have been shown to be independent predictors
of death in both study groups. Because patients with sepsis and septic
shock have higher plasma concentrations (2.3- and 4.2-fold,
respectively) than those expected on the basis of their fat mass, it
has been postulated that, in this case, circulating leptin does not
signal the magnitude of energy stores to the hypothalamus but works
rather as a stress-related peptide. Survivors of severe sepsis and
septic shock exhibited leptin concentrations 1.3- and 1.6-fold greater
than nonsurvivors in each group (5). Thus the leptin
response may be related to the extent of activation of the immune
system and may serve as a marker of the severity and outcome of septic
patients (5), because leptin has been shown to stimulate
proliferation of lymphohematopoetic cells and phagocytic activity of
macrophages (46).
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CYTOKINES IN ENERGY REGULATION |
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TOP
ABSTRACT
OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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Although adipose tissue consumes little oxygen relative to other organs, it is an exceptionally efficient participant in the regulation of fuel selection in whole body physiology (38). Adipose tissue has the ability to regulate its metabolism, cell size, and cell number through the production of autocrine, paracrine, and endocrine signals. By participating in food intake regulation, the adipocyte literally controls the substrate flow available for storage of triglycerides.
Obesity results from both quantitative and qualitative changes at the
adipose tissue level. An excess of adipose tissue frequently includes
both hyperplasic and hypertrophic development (14, 22).
This circumstance tends to exacerbate the overproduction of cytokines
and other mediators, with the potential of exerting their effects both
locally and systemically, and thus promoting the pathophysiological
complications associated with increased fat mass (Fig.
5). As mentioned above, the efficiency of
fat deposition is affected by local secretion of adipocyte-derived
factors, which influence insulin signaling, decrease lipogenic gene
expression, increase lipolysis, control blood flow, and regulate
intracellular triglyceride synthesis. The mechanisms that lead to
obesity are complex and involve multiple cytokines, hormones, and
growth factors. The fact that TNF-, leptin, IL-6, insulin, PAI-1,
TGF-, and the like are elevated in obesity and induce other
adipocyte-derived products in both plasma and adipose tissue reveals
the participation of a highly intricate network of signals in the
regulation of obesity. Undoubtedly, there are many other mechanisms and
factors that regulate the level of energy stores by modulating the
deposition and mobilization of adipose triglyceride pools and that need
to be uncovered.
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EFFECTS OF CYTOKINES ON INSULIN SIGNALING |
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ABSTRACT
OVERVIEW
WHITE ADIPOSE TISSUE SIGNALS
ADIPOCYTE SECRETORY PRODUCTS...
ADIPOCYTES AS A SOURCE...
CROSS TALK AMONG ADIPOCYTE-...
CYTOKINES IN ENERGY REGULATION
EFFECTS OF CYTOKINES ON...
CROSS TALK WITH NEUROENDOCRINE...
CONCLUDING REMARKS
REFERENCES
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There is growing experimental evidence from animal studies that
TNF- plays a key role in the pathogenesis of insulin resistance associated with obesity (69). Hotamisligil et al.
(65) were the first to report a close relationship between
increased adipose TNF- expression and features of insulin resistance
in rodent models of obesity and type 2 diabetes mellitus
(65). In obese fa/fa rats, insulin resistance
could be reversed by infusion of a TNF--neutralizing IgG fusion
protein containing soluble TNFR domains. Subsequent investigations
showed that TNF- interferes with the tyrosine phosphorylation of the
insulin receptor in Fao hepatocytes and 3T3 cells (35).
Further experiments demonstrated that TNF- induces phosphorylation
of insulin receptor substrate-1 (IRS-1) at serine residues and that
serine-phosphorylated IRS-1 operates as an inhibitor of insulin
receptor activity (64, 80). By use of a fibroblast cell
line overexpressing the human insulin receptor, a role for
phosphotyrosine phosphatases in the TNF-mediated inhibition of insulin
signaling has been postulated (90). Furthermore, in
response to acute insulin stimulation after cellular TNF- exposure,
a normal tyrosine phosphorylation of the insulin receptor and IRS-1,
together with a reduced expression of proteins involved in insulin
action, such as IRS-1 and GLUT-4, has been reported, representing a
plausible explanation for the observed insulin resistance of glucose
transport (155). The potential role of IRS-2 in
TNF-induced insulin resistance has yielded conflicting results.
Although in hepatoma cells and brown adipocytes IRS-2 has been shown to
be involved in the induction of insulin resistance through TNF-
