Doi:10.1016/j.coph.2005.01.006

Adipose tissue as an active endocrine organ: recent advancesRuth E Gimeno and Lori D Klaman Adipose tissue secretes a variety of factors in a manner physiology and pharmacology of adipose-derived factors dependent upon its metabolic state. These factors are derived with particular emphasis on their therapeutic potential.
from adipocyte or non-adipocyte fractions, and includeproteins, metabolites and hormones. Obesity is a major risk factor for type 2 diabetes and cardiovascular disease, and Leptin, the 16 kDa product of the ob gene, signals adipocyte-derived factors might contribute to or ameliorate through central pathways to control satiety, energy obesity-associated pathologies such as insulin resistance, expenditure and neuroendocrine function. The mechan- dyslipidemia, vascular dysfunction and a chronic inflammatory ism of leptin action in the hypothalamus and its effects on satiety have been discussed elsewhere [Leptin hasprofound effects on lipid metabolism, which are mediatedthrough both central and peripheral pathways []. In AddressesDepartment of Cardiovascular and Metabolic Diseases, Wyeth muscle, leptin stimulates fatty acid oxidation by activat- Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA ing 50-activated AMP kinase (AMPK) both directly andthrough a central mechanism Leptin also partitions Corresponding author: Gimeno, RE (rgimeno@wyeth.com) lipids away from non-adipose tissue, thus averting lipo-toxicity; this effect might be mediated by its ability torepress stearoyl CoA desaturase through a central path- Current Opinion in Pharmacology 2005, 5:122–128 way ]. In addition, leptin has been shown recently to inhibit hepatic triglyceride accumulation directly by acti- vating phosphatidylinositol-3-kinase [Interestingly, Edited by Robert Scarborough and George Vlasuk leptin has both deleterious and protective effects oncardiovascular function ]. Leptin-deficient mice, whileobese, are resistant to hypertension, thrombosis and impaired fibrinolysis; leptin administration in these mice # 2005 Elsevier Ltd. All rights reserved.
promotes neointimal growth and stenosis ], whereas inhibition of leptin using neutralizing antibodies protectswild-type mice from thrombosis [together suggestinga prothrombotic function for leptin. Conversely, leptindeficiency is associated with cardiac hypertrophy, and leptin supplementation reverses that phenotype, suggest- Starting with the discovery of leptin as an adipocyte- ing an antihypertrophic function ]. The use of leptin as derived satiety factor, adipose tissue is increasingly being a therapeutic agent is limited by the severe leptin resis- recognized as an endocrine organ. A growing number of tance present in most obese individuals and, to date, adipocyte-derived factors have been described and their leptin therapy has been used successfully only in patients contribution to the pathophysiology of the metabolic with genetic leptin deficiency or lipodystrophy [ syndrome, characterized by central adiposity, insulinresistance, dyslipidemia, hypertension, chronic inflamma- tion and a prothrombotic state, is being investigated.
Adiponectin (ACRP30/AdipoQ) is a 30 kDa protein speci- Apart from fully differentiated adipocytes, adipose tissue fically expressed in adipocytes, plasma levels of which contains numerous other cell types, including fibroblasts, negatively correlate with adiposity, insulin resistance, cor- onary artery disease and dyslipidemia in both mice and smooth muscle cells. It is becoming increasingly clear humans [In mice, deletion of adiponectin results in that several adipose-derived factors are not, or at least not insulin resistance, dyslipidemia and increased neointimal exclusively, produced by adipocytes; in addition, some proliferation, whereas overexpression or pharmacological factors might primarily act by inducing secretion of other administration of adiponectin improves insulin sensitivity factors within adipose tissue in an autocrine or paracrine and protects against atherosclerosis Recently, fashion. Different adipose depots are functionally dis- a protective role for adiponectin in cardiomyopathy was tinct; visceral adipose tissue is of particular interest, as its demonstrated: adiponectin deletion enhances cardiac mass is most closely associated with the metabolic syn- hypertrophy, whereas overexpression attenuates it ]; drome. Several excellent reviews on adipose-derived furthermore, in vitro, adiponectin modulates hypertrophic factors have been published recently and will be referred signals in cardiomyocytes. Adiponectin also stimulates to [This review focuses on recent advances in the angiogenesis and is important for recovery from ischaemic Current Opinion in Pharmacology 2005, 5:122–128 Adipose tissue as an active endocrine organ: recent advances Gimeno and Klaman injury ]. Under different conditions, however, adipo- part of a family of resistin-like-molecules (RELMs), which nectin can also be antiangiogenic Adiponectin is contains four members in the mouse, but only two in thought to directly affect a wide variety of target cells, humans. Importantly, resistin can heterodimerize with including hepatocytes, myocytes, endothelial cells, macro- some RELM family members [], and at least one resistin phages and smooth muscle cells; AMPK has been identi- homologue, RELMb, has been shown to have effects on fied as a key intracellular mediator of adiponectin function insulin resistance indistinguishable from those of resistin ]. Recently, the notion of a primarily peripheral action []. Although recent studies clearly establish a role for of adiponectin has been challenged by the finding that murine resistin in glucose metabolism, and possibly dysli- central injection of adiponectin modulates energy expen- pidemia [], translation of these results into diture, resulting in decreased body weight []. It will be humans has been questioned given the differences important to determine whether central effects of adipo- between mouse and human tissue distribution. Human nectin also contribute to its effects on glucose metabolism resistin serum levels are associated with adiposity and insulin resistance in many, but not all, studies [Inter-estingly, human resistin is induced by inflammatory med- The study of adiponectin is complicated by the hetero- iators such as lipopolysaccharide and tumour necrosis geneity of protein preparations. Adiponectin assembles factor (TNF)a [], raising the possibility that upregula- into trimers, hexamers and larger high molecular weight tion of human resistin in obesity is secondary to upregula- (HMW) structures, and is modified by hydroxylation and tion of inflammatory mediators. Human resistin promotes glycosylation []; the isoform composition of smooth muscle cell proliferation ] and endothelial cell different preparations varies depending upon the source activation supporting a possible proatherogenic role of protein. Full-length trimeric adiponectin can also be for resistin. The crystal structure of resistin has recently processed proteolytically to a 26 kDa form in mammalian been determined []; similar to adiponectin, resistin cells [], and a 16 kDa tryptic digestion fragment forms multimeric complexes, and is present in mouse (globular adiponectin) has been used in numerous studies serum as two distinct isoforms, most likely trimers and An area of significant interest is the physiological hexamers. A mutant that is unable to form hexamers is effects of different adiponectin isoforms. The ratio of more potent in inducing insulin resistance than is the wild- HMW to total adiponectin is significantly decreased in type protein, suggesting processing-mediated activation patients with coronary artery disease [and increases []. Although no receptors for resistin have been iden- upon treatment with thiazoledinediones []. The tified, AMPK has been suggested as an important intra- HMW form mediates adiponectin effects in liver and cellular mediator []. An emerging theme is a functional antagonism between resistin and adiponectin; it will be appear to be the primary mediators in heart, skeletal interesting to see whether different isoforms of resistin have distinct receptors and signaling activities as has been a preparation containing the 26 kDa processed fragment is more potent in the liver than is HMW adiponectin,possibly indicating an important role for proteolytic pro- cessing []. Two adiponectin receptors, AdipoR1 and Angiopoietin-like protein 4 (ANGPTL4; FIAF/PGAR), a AdipoR2, have been identified []. These receptors 50 kDa secreted protein highly expressed in adipose show a different affinity for globular and full-length tissue, is an angiopoietin family member most closely adiponectin, and differ in their tissue distribution, which related to ANGPTL3 []. Expression of ANGPTL4 might explain the varying effects of different isoforms.
is directly regulated by members of the PPAR family of However, the affinity of these receptors for individual transcription factors ]; however, regulation by mammalian-derived adiponectin isoforms remains to be adipose mass or nutritional status is not consistently found determined. T-cadherin was recently suggested as an []. Similar to ANGPTL3, overexpression of additional adiponectin receptor, on the basis of its ability ANPTL4 dramatically increases plasma triglyceride to bind HMW, but not trimeric, adiponectin [how- levels, possibly owing to direct inhibition of lipoprotein ever, its signaling abilities have not yet been examined. In lipase [It remains unclear, however, whether the addition to utilizing different receptors, different isoforms levels achieved by overexpression are physiologically of adiponectin can also activate distinct signal transduc- relevant. ANGPTL4 also has antiangiogenic activities tion pathways: in muscle, HMW adiponectin activates the []. Structural studies and comparison to ANGPTL3 nuclear factor-kB pathway, whereas trimeric forms acti- suggests that the N-terminal coiled-coil domain is respon- sible for the triglyceride increase, whereas the C-terminalfibrinogen-like domain mediates the antiangiogenic effect []. Interestingly, ANGPTL4 is processed in a Resistin is a 10 kDa protein that is secreted exclusively tissue- and species-specific manner [], and this proces- by adipocytes in the mouse, but is expressed primarily in sing might enhance in vivo activity []. The physiolo- macrophages and monocytes in humans [Resistin is gical role of ANGPTL4 remains to be elucidated.
Current Opinion in Pharmacology 2005, 5:122–128 enters the systemic circulation and mediates obesity- Visfatin (pre-B cell colony-enhancing factor), a 52 kDa associated metabolic and cardiovascular disorders. TNFa secreted protein, was recently added to the list of adipo- is an important mediator of inflammation and can induce cyte-derived factors []. Although visfatin is widely several other inflammatory cytokines However, expressed, adipose visfatin is specific to the visceral depot, although circulating TNFa clearly is important for the and visfatin serum levels are positively correlated with development of insulin resistance in rodents, several visceral adiposity. Visfatin has effects similar to insulin, human studies did not show any beneficial effects on and can bind to and activate the insulin receptor at a site insulin sensitivity when circulating TNFa was neutralized distinct from insulin. Because the circulating levels of ], leading to the suggestion that TNFa acts in a para- visfatin are significantly lower than its affinity for the crine fashion. A recent report proposed that prolonged insulin receptor, visfatin might act in an auto- or paracrine treatment might be required to detect an effect of anti- manner, rather than in an endocrine fashion. Visfatin TNFa treatment on insulin sensitivity IL-6 is also expression is regulated in inflammation and sepsis, and secreted by adipose tissue at high levels [] and is present visfatin can inhibit apoptosis in neutrophils, implying in the systemic circulation at higher levels than TNFa.
functions other than its insulin-mimetic effects [].
IL-6 has been implicated in the regulation of insulinsensitivity and possibly body weight in rodents, and both peripheral and central actions of IL-6 might be involved Free fatty acids (FFAs) released from adipose tissue are a Although neutralizing anti-IL-6 antibodies have major source of plasma FFAs, and adipose tissue FFA been developed, their effect on obesity-associated disor- release as well as plasma FFA levels are elevated in obese ders has not yet been evaluated. The effects of inflamma- individuals Elevated plasma FFA levels can cause tory mediators on cells of interest to cardiovascular disease insulin resistance in muscle and liver; this is mediated have recently been reviewed []. Adipose tissue-derived by intracellular fatty acid metabolites such as acyl-CoA complement components, most notably Factor D/Adipsin, and possibly ceramide [In addition, FFA infusion and the complement-derived factor acylation-stimulating decreases mitochondrial gene expression in muscle [], suggesting that FFAs may modulate the metaboliccapacity of target tissues. FFAs have also been implicated in the pathogenesis of cardiomyopathy, and genetic mod- Plasminogen-activator inhibitor 1 (PAI-1) is a serine els that increase fatty acid delivery to heart recapitulate protease inhibitor that prevents plasmin generation and many of the features of diabetic cardiomyopathy [].
plasmin-mediated events such as fibrinolysis and extra- Circulating FFAs are almost exclusively derived from cellular matrix degradation; elevated plasma PAI-1 levels subcutaneous adipose tissue [thus FFA lipolysis is are a known risk factor for thrombosis ]. PAI-1 might unlikely to account for the association between visceral also regulate fibrin deposition and vascular smooth mus- adiposity and metabolic syndrome disorders.
cle cell function through direct interactions with vitro-nectin ]. Although PAI-1 is synthesized by many cell types, adipose tissue is thought to be a major source of PAI-1 in the obese, and circulating PAI-1 levels correlate Obesity is well recognized as a state of low-grade inflamma- with visceral adiposity [Within obese adipose tissue, tion. Adipose tissue expresses a large variety of cytokines both adipocyte and non-adipocyte fractions produce PAI- and chemokines (e.g. TNFa, interleukin [IL]-1b, IL-6, IL- 1 [], and TNFa is a key mediator of obesity-linked 8, IL-10, IL-1 receptor antagonist, monocyte chemotactic elevation of PAI-1 []. Recent attention has focused on protein-1, macrophage migration inhibitory factor, macro- the possible role of PAI-1 in adipose tissue development.
phage inflammatory protein 1a, and macrophage inflam- In response to a high-fat diet, PAI-1-deficient mice show matory protein-related protein-2), as well as acute phase less weight gain, smaller adipocyte size and lower tissue reactants (e.g. serum amyloid A3, haptoglobin), and many of triglyceride levels compared with wild-type mice, these are known to be upregulated in both adipose tissue whereas energy expenditure and insulin sensitivity are and the systemic circulation in obesity Recent studies increased [Small molecule inhibitors of PAI-1 demonstrate that obesity is associated with macrophage have been developed and shown to be efficacious in infiltration into adipose tissue in both mice and humans animal models of thrombosis ]. It will be interesting [Many, but not all, of the factors cited above are to see whether these inhibitors also ameliorate obesity.
produced primarily by adipose tissue macrophages ratherthan adipocytes []. Macrophages appear to Glucocorticoids and the renin-angiotensin be recruited from the circulation and adipocyte-derived factors might be involved in this process [ Localized glucocorticoid production by adipose tissue,mediated by the enzyme 11-b-hydroxysteroid dehydro- An important unanswered question is the degree to which genase 1 (11b-HSD1), is an important regulator of meta- any particular adipose-derived inflammatory mediator bolic syndrome components in rodents, and possibly Current Opinion in Pharmacology 2005, 5:122–128 Adipose tissue as an active endocrine organ: recent advances Gimeno and Klaman humans ]. Importantly, systemic glucocorticoid Havel PJ: Update on adipocyte hormones. Regulation ofenergy balance and carbohydrate/lipid metabolism.
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Demonstrates macrophage infiltration in adipose tissue in several mouse Careful analysis of the phenotype of 11b-HSD1-deficient mice in two models of obesity; macrophage infiltration can be reversed by treatment different genetic backgrounds shows decreased adiposity owing to increased energy expenditure, improved insulin sensitivity, improved lipidprofile, and beneficial changes in adipose expression of adiponectin, 57. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, resistin, leptin, peroxisome proliferator-activated receptor-g and TNFa.
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73. Goossens GH, Blaak EE, van Baak MA: Possible involvement of 75. Gollasch M, Dubrovska G: Paracrine role for periadventitial the adipose tissue renin-angiotensin system in the adipose tissue in the regulation of arterial tone. Trends pathophysiology of obesity and obesity-related disorders.
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