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Adiponectin Receptor as a Key Player in Healthy Longevity and Obesity-Related Diseases

2013; Cell Press; Volume: 17; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2013.01.001

1932-7420

Toshimasa Yamauchi, Takashi Kadowaki,

Regulation of Appetite and Obesity

Adiponectin is a fat-derived hormone whose reduction plays central roles in obesity-linked diseases including insulin resistance/type 2 diabetes and atherosclerosis. The cloning of Adiponectin receptors AdipoR1 and AdipoR2 has stimulated adiponectin research, revealing pivotal roles for AdipoRs in pleiotropic adiponectin actions, as well as some postreceptor signaling mechanisms. Adiponectin signaling has thus become one of the major research fields in metabolism and clinical medicine. Studies on AdipoRs will further our understanding of the role of adiponectin in obesity-linked diseases and shortened life span and may guide the design of antidiabetic and antiaging drugs with AdipoR as a target. Adiponectin is a fat-derived hormone whose reduction plays central roles in obesity-linked diseases including insulin resistance/type 2 diabetes and atherosclerosis. The cloning of Adiponectin receptors AdipoR1 and AdipoR2 has stimulated adiponectin research, revealing pivotal roles for AdipoRs in pleiotropic adiponectin actions, as well as some postreceptor signaling mechanisms. Adiponectin signaling has thus become one of the major research fields in metabolism and clinical medicine. Studies on AdipoRs will further our understanding of the role of adiponectin in obesity-linked diseases and shortened life span and may guide the design of antidiabetic and antiaging drugs with AdipoR as a target. The prevalence of obesity has increased dramatically in recent years (Friedman, 2000Friedman J.M. Obesity in the new millennium.Nature. 2000; 404: 632-634Crossref PubMed Scopus (610) Google Scholar). It is commonly associated with type 2 diabetes, dyslipidemia, and hypertension, and the coexistence of these diseases has been termed metabolic syndrome, which is related to atherosclerosis (Reaven, 1997Reaven G.M. Role of insulin resistance in human disease - Syndrome X revisited.Atherosclerosis. 1997; 134: 3Abstract Full Text PDF Google Scholar; Matsuzawa, 1997Matsuzawa Y. Pathophysiology and molecular mechanisms of visceral fat syndrome: the Japanese experience.Diabetes Metab. Rev. 1997; 13: 3-13Crossref PubMed Scopus (171) Google Scholar). In addition to metabolic syndrome and atherosclerosis, obesity has been reported to be associated with a wide spectrum of health problems such as cancer, fatty liver, and Alzheimer’s disease. Insulin resistance is a key feature of these diseases and is defined as a state in which greater than normal insulin levels are required to maintain glucose homeostasis. To compensate for this insulin resistance, insulin secretion is increased, leading to hyperinsulinemia. Thus, insulin resistance and hyperinsulinemia are seen to coexist in obesity. The reduced cellular insulin response due to insulin resistance results in insufficient inhibition of gluconeogenesis in the liver and decreased glucose uptake in skeletal muscle, leading to type 2 diabetes, thereby forming “the vicious circle.” In contrast, the excessive insulin levels result in cell proliferation and increased cellular stress such as oxidative stress and ectopic fat accumulation in vascular smooth muscle cells, cancer cells, hepatocytes, and neuronal cells, leading to atherosclerosis, cancer, dyslipidemia, fatty liver, and Alzheimer’s disease. Before “the vicious circle” is formed, what is the mechanism by which obesity first results in insulin resistance (and then induces hyperinsulinemia)? White adipose tissue (WAT) is a major site of energy storage and is important for energy homeostasis: it stores energy in the form of triglycerides during nutritional abundance and releases it as free fatty acids (FFAs) during nutritional deprivation (Kahn, 2000Kahn C.R. Triglycerides and toggling the tummy.Nat. Genet. 2000; 25: 6-7Crossref PubMed Scopus (25) Google Scholar; Spiegelman and Flier, 2001Spiegelman B.M. Flier J.S. Obesity and the regulation of energy balance.Cell. 2001; 104: 531-543Abstract Full Text Full Text PDF PubMed Scopus (1816) Google Scholar). While WAT provides a survival advantage in times of starvation, excess WAT is now linked to obesity-related health problems in the current nutritionally rich environment. Regulated by multiple hormonal signals, nuclear hormone receptors, and the central nervous system, WAT has been increasingly recognized as an important endocrine organ that secretes a number of biologically active “adipokines” (Hotamisligil et al., 1993Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Scopus (5740) Google Scholar; Zhang et al., 1994Zhang Y.Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (11223) Google Scholar; Lazar, 2006Lazar M.A. The humoral side of insulin resistance.Nat. Med. 2006; 12: 43-44Crossref PubMed Scopus (64) Google Scholar). Some of these adipokines have been shown to directly or indirectly affect insulin sensitivity through modulation of insulin signaling and the molecules involved in glucose and lipid metabolism. Of these adipokines, adiponectin has recently attracted much attention because of its antidiabetic and antiatherogenic effects as well as its antiproliferative effects in cancer cells and is expected to be a therapeutic tool for diabetes, metabolic syndrome, cardiovascular diseases, and cancers (Kadowaki and Yamauchi, 2005Kadowaki T. Yamauchi T. Adiponectin and adiponectin receptors.Endocr. Rev. 2005; 26: 439-451Crossref PubMed Scopus (1995) Google Scholar; Kadowaki et al., 2006Kadowaki T. Yamauchi T. Kubota N. Hara K. Ueki K. Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.J. Clin. Invest. 2006; 116: 1784-1792Crossref PubMed Scopus (2090) Google Scholar). Adiponectin, also termed Acrp30 (Scherer et al., 1995Scherer P.E. Williams S. Fogliano M. Baldini G. Lodish H.F. A novel serum protein similar to C1q, produced exclusively in adipocytes.J. Biol. Chem. 1995; 270: 26746-26749Crossref PubMed Scopus (2607) Google Scholar), AdipoQ (Hu et al., 1996Hu E. Liang P. Spiegelman B.M. AdipoQ is a novel adipose-specific gene dysregulated in obesity.J. Biol. Chem. 1996; 271: 10697-10703Crossref PubMed Scopus (1823) Google Scholar), apM1 (Maeda et al., 1996Maeda K. Okubo K. Shimomura I. Funahashi T. Matsuzawa Y. Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).Biochem. Biophys. Res. Commun. 1996; 221: 286-289Crossref PubMed Scopus (1792) Google Scholar), or GBP28 (Nakano et al., 1996Nakano Y. Tobe T. Choi-Miura N.H. Mazda T. Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma.J. Biochem. 1996; 120: 803-812Crossref PubMed Scopus (758) Google Scholar), was originally identified independently by four groups using different approaches. The Adiponectin gene encodes a secreted protein expressed exclusively in both WAT and brown adipose tissue. Adiponectin has a carboxyl-terminal globular domain and an amino-terminal collagen domain and is structurally similar to complement 1q (Shapiro and Scherer, 1998Shapiro L. Scherer P.E. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor.Curr. Biol. 1998; 8: 335-338Abstract Full Text Full Text PDF PubMed Google Scholar), which belongs to a family of proteins that form characteristic multimers (McCormack et al., 1997McCormack F.X. Pattanajitvilai S. Stewart J. Possmayer F. Inchley K. Voelker D.R. The Cys6 intermolecular disulfide bond and the collagen-like region of rat SP-A play critical roles in interactions with alveolar type II cells and surfactant lipids.J. Biol. Chem. 1997; 272: 27971-27979Crossref PubMed Scopus (62) Google Scholar). In contrast to the expression of adipokines such as tumor necrosis factor-α (TNF-α) and MCP-1, which cause insulin resistance, adiponectin expression is reduced in obese, insulin-resistant rodent models (Hu et al., 1996Hu E. Liang P. Spiegelman B.M. AdipoQ is a novel adipose-specific gene dysregulated in obesity.J. Biol. Chem. 1996; 271: 10697-10703Crossref PubMed Scopus (1823) Google Scholar). Plasma adiponectin levels have also been reported to be reduced in obese humans (Arita et al., 1999Arita Y. Kihara S. Ouchi N. Takahashi M. Maeda K. Miyagawa J. Hotta K. Shimomura I. Nakamura T. Miyaoka K. et al.Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.Biochem. Biophys. Res. Commun. 1999; 257: 79-83Crossref PubMed Scopus (3923) Google Scholar). Importantly, decrease in plasma adiponectin levels preceded the onset of diabetes in obese rhesus monkey model, in parallel with the observation of decreased insulin sensitivity (Hotta et al., 2001Hotta K. Funahashi T. Bodkin N.L. Ortmeyer H.K. Arita Y. Hansen B.C. Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys.Diabetes. 2001; 50: 1126-1133Crossref PubMed Scopus (940) Google Scholar). Using DNA chips, we screened for secreted molecules in WAT, the expressions of which were increased in small adipocytes from insulin sensitive mice such as heterozygous peroxisome proliferator-activated receptor γ (PPARγ)-deficient mice, and we found that increased expression of adiponectin correlates with increased insulin sensitivity in mouse models of altered insulin sensitivity. We next assessed whether adiponectin was able to improve insulin resistance in KKAy mice (KK mice overexpressing the agouti protein), as a model of the metabolic syndrome and type 2 diabetes linked to obesity. Plasma adiponectin levels were decreased in KKAy mice fed a high-fat diet (HFD). Replenishment of adiponectin significantly ameliorated HFD-induced insulin resistance and hypertriglyceridemia, which led us to propose that adiponectin is an insulin-sensitizing adipokine (Yamauchi et al., 2001Yamauchi T. Kamon J. Waki H. Terauchi Y. Kubota N. Hara K. Mori Y. Ide T. Murakami K. Tsuboyama-Kasaoka N. et al.The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.Nat. Med. 2001; 7: 941-946Crossref PubMed Scopus (3886) Google Scholar). These data also strongly suggested that the HFD-induced, obesity-linked decrease in adiponectin level is causally involved in obesity-linked insulin resistance and the metabolic syndrome. Scherer and colleagues reported that an acute increase in the level of circulating adiponectin triggers a transient decrease in basal glucose level by inhibiting both the expression of hepatic gluconeogenic enzymes and the rate of endogenous glucose production in both wild-type and type 2 diabetic mice, and they proposed that adiponectin sensitizes the body to insulin, which is associated with inhibition of endogenous glucose production (Berg et al., 2001Berg A.H. Combs T.P. Du X.L. Brownlee M. Scherer P.E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.Nat. Med. 2001; 7: 947-953Crossref PubMed Scopus (2137) Google Scholar; Combs et al., 2001Combs T.P. Berg A.H. Obici S. Scherer P.E. Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30.J. Clin. Invest. 2001; 108: 1875-1881Crossref PubMed Scopus (763) Google Scholar). Lodish and colleagues reported that a proteolytic cleavage product of adiponectin, which structurally resembles globular adiponectin, increases fatty acid oxidation in muscle, decreases plasma glucose, and causes weight loss in mice (Fruebis et al., 2001Fruebis J. Tsao T.S. Javorschi S. Ebbets-Reed D. Erickson M.R.S. Yen F.T. Bihain B.E. Lodish H.F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.Proc. Natl. Acad. Sci. USA. 2001; 98: 2005-2010Crossref PubMed Scopus (1690) Google Scholar). Subsequently, the long-term effects of adiponectin on insulin resistance in vivo were investigated through the use of adiponectin transgenic mice (Yamauchi et al., 2003aYamauchi T. Kamon J. Waki H. Imai Y. Shimozawa N. Hioki K. Uchida S. Ito Y. Takakuwa K. Matsui J. et al.Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.J. Biol. Chem. 2003; 278: 2461-2468Crossref PubMed Scopus (772) Google Scholar; Combs et al., 2004Combs T.P. Pajvani U.B. Berg A.H. Lin Y. Jelicks L.A. Laplante M. Nawrocki A.R. Rajala M.W. Parlow A.F. Cheeseboro L. et al.A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity.Endocrinology. 2004; 145: 367-383Crossref PubMed Scopus (426) Google Scholar) or adiponectin-deficient mice (Kubota et al., 2002Kubota N. Terauchi Y. Yamauchi T. Kubota T. Moroi M. Matsui J. Eto K. Yamashita T. Kamon J. Satoh H. et al.Disruption of adiponectin causes insulin resistance and neointimal formation.J. Biol. Chem. 2002; 277: 25863-25866Crossref PubMed Scopus (1153) Google Scholar; Maeda et al., 2002Maeda N. Shimomura I. Kishida K. Nishizawa H. Matsuda M. Nagaretani H. Furuyama N. Kondo H. Takahashi M. Arita Y. et al.Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.Nat. Med. 2002; 8: 731-737Crossref PubMed Scopus (1756) Google Scholar; Ma et al., 2002Ma K. Cabrero A. Saha P.K. Kojima H. Li L. Chang B.H.J. Paul A. Chan L. Increased beta -oxidation but no insulin resistance or glucose intolerance in mice lacking adiponectin.J. Biol. Chem. 2002; 277: 34658-34661Crossref PubMed Scopus (268) Google Scholar; Nawrocki et al., 2006Nawrocki A.R. Rajala M.W. Tomas E. Pajvani U.B. Saha A.K. Trumbauer M.E. Pang Z. Chen A.S. Ruderman N.B. Chen H. et al.Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists.J. Biol. Chem. 2006; 281: 2654-2660Crossref PubMed Scopus (498) Google Scholar). Adiponectin transgenic mice showed amelioration of insulin resistance and diabetes. Adiponectin-deficient mice showed mild insulin resistance with glucose intolerance. Adiponectin-deficient mice also exhibited other features of metabolic syndrome, such as dyslipidemia and hypertension (Kubota et al., 2002Kubota N. Terauchi Y. Yamauchi T. Kubota T. Moroi M. Matsui J. Eto K. Yamashita T. Kamon J. Satoh H. et al.Disruption of adiponectin causes insulin resistance and neointimal formation.J. Biol. Chem. 2002; 277: 25863-25866Crossref PubMed Scopus (1153) Google Scholar). Scherer and his colleagues reported that adiponectin transgenic mice displayed increased expression of PPARγ target genes and became morbidly obese with improvement in insulin sensitivity (Kim et al., 2007Kim J.-Y. van de Wall E. Laplante M. Azzara A. Trujillo M.E. Hofmann S.M. Schraw T. Durand J.L. Li H. Li G. et al.Obesity-associated improvements in metabolic profile through expansion of adipose tissue.J. Clin. Invest. 2007; 117: 2621-2637Crossref PubMed Scopus (921) Google Scholar). Plasma adiponectin levels have also been reported to be reduced in obese humans, particularly those with visceral obesity, and to correlate inversely with insulin resistance (Arita et al., 1999Arita Y. Kihara S. Ouchi N. Takahashi M. Maeda K. Miyagawa J. Hotta K. Shimomura I. Nakamura T. Miyaoka K. et al.Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.Biochem. Biophys. Res. Commun. 1999; 257: 79-83Crossref PubMed Scopus (3923) Google Scholar; Matsuzawa, 2010Matsuzawa Y. Establishment of a concept of visceral fat syndrome and discovery of adiponectin.Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2010; 86: 131-141Crossref PubMed Scopus (100) Google Scholar). Prospective and longitudinal studies (Lindsay et al., 2002Lindsay R.S. Funahashi T. Hanson R.L. Matsuzawa Y. Tanaka S. Tataranni P.A. Knowler W.C. Krakoff J. Adiponectin and development of type 2 diabetes in the Pima Indian population.Lancet. 2002; 360: 57-58Abstract Full Text Full Text PDF PubMed Scopus (930) Google Scholar; Spranger et al., 2003Spranger J. Kroke A. Möhlig M. Bergmann M.M. Ristow M. Boeing H. Pfeiffer A.F.H. Adiponectin and protection against type 2 diabetes mellitus.Lancet. 2003; 361: 226-228Abstract Full Text Full Text PDF PubMed Scopus (897) Google Scholar) have shown that lower adiponectin levels are associated with a higher incidence of diabetes. Adiponectin has been shown to be significantly related to the development of type 2 diabetes in Pima Indians (Lindsay et al., 2002Lindsay R.S. Funahashi T. Hanson R.L. Matsuzawa Y. Tanaka S. Tataranni P.A. Knowler W.C. Krakoff J. Adiponectin and development of type 2 diabetes in the Pima Indian population.Lancet. 2002; 360: 57-58Abstract Full Text Full Text PDF PubMed Scopus (930) Google Scholar). Hypoadiponectinemia has also been demonstrated to be independently associated with metabolic syndrome—indeed, more strongly than are any other inflammatory markers (Matsushita et al., 2006Matsushita K. Yatsuya H. Tamakoshi K. Wada K. Otsuka R. Takefuji S. Sugiura K. Kondo T. Murohara T. Toyoshima H. Comparison of circulating adiponectin and proinflammatory markers regarding their association with metabolic syndrome in Japanese men.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 871-876Crossref PubMed Scopus (147) Google Scholar). Reduced plasma adiponectin levels are also commonly observed in a variety of states frequently associated with insulin resistance, such as dyslipidemia (Matsushita et al., 2006Matsushita K. Yatsuya H. Tamakoshi K. Wada K. Otsuka R. Takefuji S. Sugiura K. Kondo T. Murohara T. Toyoshima H. Comparison of circulating adiponectin and proinflammatory markers regarding their association with metabolic syndrome in Japanese men.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 871-876Crossref PubMed Scopus (147) Google Scholar), cardiovascular disease (Matsuzawa, 2010Matsuzawa Y. Establishment of a concept of visceral fat syndrome and discovery of adiponectin.Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2010; 86: 131-141Crossref PubMed Scopus (100) Google Scholar; Pischon et al., 2004Pischon T. Girman C.J. Hotamisligil G.S. Rifai N. Hu F.B. Rimm E.B. Plasma adiponectin levels and risk of myocardial infarction in men.JAMA. 2004; 291: 1730-1737Crossref PubMed Scopus (1471) Google Scholar), and hypertension (Adamczak et al., 2003Adamczak M. Wiecek A. Funahashi T. Chudek J. Kokot F. Matsuzawa Y. Decreased plasma adiponectin concentration in patients with essential hypertension.Am. J. Hypertens. 2003; 16: 72-75Crossref PubMed Scopus (355) Google Scholar). The reduction of plasma concentrations of adiponectin is not only closely related to disease states such as type 2 diabetes and cardiovascular diseases, but is also implicated in cancer development in human obesity. Recent clinical studies involving several independent cohorts have demonstrated that plasma concentrations of adiponectin are inversely correlated with the risk of several types of cancer (Paz-Filho et al., 2011Paz-Filho G. Lim E.L. Wong M.L. Licinio J. Associations between adipokines and obesity-related cancer.Front. Biosci. 2011; 16: 1634-1650Crossref PubMed Scopus (124) Google Scholar). Plasma adiponectin levels are reduced in obesity and are even lower in patients with hepatic steatosis or nonalcoholic steatohepatitis (NASH) (Belfort et al., 2006Belfort R. Harrison S.A. Brown K. Darland C. Finch J. Hardies J. Balas B. Gastaldelli A. Tio F. Pulcini J. et al.A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.N. Engl. J. Med. 2006; 355: 2297-2307Crossref PubMed Scopus (1294) Google Scholar). Interestingly, there was an inverse relationship between the reduction in hepatic fat content and the increase in the plasma adiponectin level when patients were treated with thiazolidinedione (TZD) (Belfort et al., 2006Belfort R. Harrison S.A. Brown K. Darland C. Finch J. Hardies J. Balas B. Gastaldelli A. Tio F. Pulcini J. et al.A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.N. Engl. J. Med. 2006; 355: 2297-2307Crossref PubMed Scopus (1294) Google Scholar). From these data, we proposed adiponectin hypothesis (Kadowaki et al., 2006Kadowaki T. Yamauchi T. Kubota N. Hara K. Ueki K. Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.J. Clin. Invest. 2006; 116: 1784-1792Crossref PubMed Scopus (2090) Google Scholar). According to this hypothesis, reduced plasma adiponectin levels in obesity play causal roles in obesity-linked diseases such as type 2 diabetes, cardiovascular diseases, and NASH. Adiponectin exists in a wide range of multimer complexes in plasma and combines via its collagen domain to create 3 major oligomeric forms: a low-molecular-weight (LMW) trimer, a middle-molecular-weight (MMW) hexamer, and a high-molecular-weight (HMW) 12- to 18-mer (Pajvani et al., 2003Pajvani U.B. Du X.L. Combs T.P. Berg A.H. Rajala M.W. Schulthess T. Engel J. Brownlee M. Scherer P.E. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity.J. Biol. Chem. 2003; 278: 9073-9085Crossref PubMed Scopus (903) Google Scholar; Waki et al., 2003Waki H. Yamauchi T. Kamon J. Ito Y. Uchida S. Kita S. Hara K. Hada Y. Vasseur F. Froguel P. et al.Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.J. Biol. Chem. 2003; 278: 40352-40363Crossref PubMed Scopus (818) Google Scholar). Importantly, HMW adiponectin has been shown to be able to activate AMP kinase most potently (Kobayashi et al., 2004Kobayashi H. Ouchi N. Kihara S. Walsh K. Kumada M. Abe Y. Funahashi T. Matsuzawa Y. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin.Circ. Res. 2004; 94: e27-e31Crossref PubMed Google Scholar; Hada et al., 2007Hada Y. Yamauchi T. Waki H. Tsuchida A. Hara K. Yago H. Miyazaki O. Ebinuma H. Kadowaki T. Selective purification and characterization of adiponectin multimer species from human plasma.Biochem. Biophys. Res. Commun. 2007; 356: 487-493Crossref PubMed Scopus (118) Google Scholar). A truncated form of adiponectin that includes the globular domain cleaved proteolytically from full-length adiponectin has been reported to exist in plasma, although in very small amounts (Fruebis et al., 2001Fruebis J. Tsao T.S. Javorschi S. Ebbets-Reed D. Erickson M.R.S. Yen F.T. Bihain B.E. Lodish H.F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.Proc. Natl. Acad. Sci. USA. 2001; 98: 2005-2010Crossref PubMed Scopus (1690) Google Scholar). The Adiponectin gene expressed exclusively in adipocytes has been reported to be regulated by transcriptional factors including C/EBPs (Saito et al., 1999Saito K. Tobe T. Yoda M. Nakano Y. Choi-Miura N.H. Tomita M. Regulation of gelatin-binding protein 28 (GBP28) gene expression by C/EBP.Biol. Pharm. Bull. 1999; 22: 1158-1162Crossref PubMed Scopus (31) Google Scholar), sterol regulatory element binding protein 1c (SREBP1c) (Seo et al., 2004Seo J.B. Moon H.M. Noh M.J. Lee Y.S. Jeong H.W. Yoo E.J. Kim W.S. Park J. Youn B.S. Kim J.W. et al.Adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element-binding protein 1c regulates mouse adiponectin expression.J. Biol. Chem. 2004; 279: 22108-22117Crossref PubMed Scopus (112) Google Scholar), and PPARγ (Maeda et al., 2001Maeda N. Takahashi M. Funahashi T. Kihara S. Nishizawa H. Kishida K. Nagaretani H. Matsuda M. Komuro R. Ouchi N. et al.PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.Diabetes. 2001; 50: 2094-2099Crossref PubMed Scopus (1467) Google Scholar) (Figure 1). Farmer and his colleagues reported that during adipocyte differentiation, SirT1 levels are decreased and PPARγ levels are increased, both of which increase endoplasmic reticulum (ER) oxidoreductase Ero1-L, thereby stimulating secretion of HMW adiponectin (Qiang et al., 2007Qiang L. Wang H. Farmer S.R. Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L alpha.Mol. Cell. Biol. 2007; 27: 4698-4707Crossref PubMed Scopus (232) Google Scholar). Scherer and his colleagues showed that there is an abundant pool of properly folded adiponectin in the secretory pathway through thiol-mediated retention and that adiponectin is covalently bound to the ER chaperone ERp44. They also showed that another ER chaperone, Ero1-Lα, plays a critical role in the release of adiponectin from ERp44 and that these chaperones play a major role in the assembly of HMW adiponectin. They also reported that one mechanism for increasing circulating levels of specific adiponectin complexes by PPARγ agonists may be selective upregulation of rate-limiting chaperones such as ERp44 and Ero1-Lα (Wang et al., 2007Wang Z.V. Schraw T.D. Kim J.-Y. Khan T. Rajala M.W. Follenzi A. Scherer P.E. Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention.Mol. Cell. Biol. 2007; 27: 3716-3731Crossref PubMed Scopus (240) Google Scholar) (Figure 1). The Adiponectin gene expressed exclusively in adipocytes has been reported to be regulated by transcriptional factors, including C/EBPs, sterol regulatory element binding protein 1c (SREBP1c), and peroxisome proliferator-activated receptor γ (PPARγ). SirT1 has recently been reported to deacetylate Lys268 and Lys293 of PPARγ and to cause selective PPARγ modulation, leading to upregulation of adiponectin. There is an abundant pool of properly folded adiponectin in the secretory pathway through thiol-mediated retention, and that adiponectin is covalently bound to the ER chaperone ERp44. Another ER chaperone, Ero1-Lα, plays a critical role in the release of adiponectin from ERp44, and that these chaperones play a major role in the assembly of HMW adiponectin. Hyperinsulinemia, oxidative stress and inflammation observed in obesity have been reported to reduce HMW adiponectin, whereas TZDs and caloric restriction have been reported to increase HMW adiponectin. Several observations support the hypothesis that HMW adiponectin is the more active form of the protein and has a more relevant role in insulin sensitivity and in protecting against diabetes. First, rare mutations—G84R and G90S—in the collagen domain are closely associated with type 2 diabetes (Waki et al., 2003Waki H. Yamauchi T. Kamon J. Ito Y. Uchida S. Kita S. Hara K. Hada Y. Vasseur F. Froguel P. et al.Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.J. Biol. Chem. 2003; 278: 40352-40363Crossref PubMed Scopus (818) Google Scholar). Subjects with either of these two mutations have extremely low levels of HMW adiponectin, although total plasma adiponectin levels were not significantly changed. Moreover, the two mutant adiponectins recombinantly expressed in NIH 3T3 fibroblasts were not able to form the HMW form of adiponectin (Waki et al., 2003Waki H. Yamauchi T. Kamon J. Ito Y. Uchida S. Kita S. Hara K. Hada Y. Vasseur F. Froguel P. et al.Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.J. Biol. Chem. 2003; 278: 40352-40363Crossref PubMed Scopus (818) Google Scholar). Second, increases in the ratio of plasma HMW adiponectin levels to total adiponectin levels correlate with improvement in insulin sensitivity during treatment with an insulin-sensitizing drug, TZD, in both mice and human diabetes, whereas increases in total serum adiponectin levels do not show good correlations with improvement in insulin sensitivity during treatment with TZD (Pajvani et al., 2004Pajvani U.B. Hawkins M. Combs T.P. Rajala M.W. Doebber T. Berger J.P. Wagner J.A. Wu M. Knopps A. Xiang A.H. Utzschneider K.M. et al.Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.J. Biol. Chem. 2004; 279: 12152-12162Crossref PubMed Scopus (982) Google Scholar). Third, the level of plasma HMW adiponectin was reported to be associated with parameters related to glucose homeostasis in a cohort study (Lara-Castro et al., 2006Lara-Castro C. Luo N. Wallace P. Klein R.L. Garvey W.T. Adiponectin multimeric complexes and the metabolic syndrome trait cluster.Diabetes. 2006; 55: 249-259Crossref PubMed Scopus (402) Google Scholar). It is noteworthy that the ratio of plasma HMW adiponectin to total adiponectin correlated more significantly with glucose and insulin levels than did the total adiponectin level (Lara-Castro et al., 2006Lara-Castro C. Luo N. Wallace P. Klein R.L. Garvey W.T. Adiponectin multimeric complexes and the metabolic syndrome trait cluster.Diabetes. 2006; 55: 249-259Crossref PubMed Scopus (402) Google Scholar), suggesting that alterations in plasma HMW adiponectin level may be more relevant to the prediction of insulin resistance than are total plasma adiponectin alterations. Consistent with this, levels of total adiponectin, HMW adiponectin, and the HMW-to-total adiponectin ratio all inversely correlated with key features of central obesity and positively correlated with the insulin-stimulated glucose disposal rate. However, HMW adiponectin levels, not total adiponectin levels, are primarily responsible for these relationships, suggesting that measurement of the HMW adiponectin level may be superior to measurement of total adiponectin (Fisher et al., 2005Fisher F.M. Trujillo M.