Physiological and pathophysiological roles ofAdiponectin receptors and identification of molecular targets for treatment of life-style related diseases

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 18209033
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: KADOWAKI Takashi The University of Tokyo, Faculty of Medicine, Professor (30185889)
• Co-Investigator(Kenkyū-buntansha): UEKI Koh jiro The University of Tokyo, Faculty of Medicine, Associate Professor (00396714) ; YAMAUCHI Toshimasa The University of Tokyo, Faculty of Medicine, Project Associate Professor (40372370) ; HARA Kazuo The University of Tokyo, Faculty of Medicine, Lecturer (50359600) ; KUBOTA Naoto The University of Tokyo, Faculty of Medicine, Project Associate Professor (50396719)
• Project Period (FY): 2006 – 2007
• Keywords: diabetes / adipokine / receptor

Research Abstract

Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. In this study, we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo (Nat. Med. 13:332, 2007).
We next examined the effects of adiponectin in the central nervous system, In this study, we show that adiponectin enhances AMPK activity in the arcuate hypothalamus (ARH) via its receptor AdipoR1 to stimulate food intake; this stimulation of food intake by adiponectin was attenuated by dominant-negative AMPK expression in the ARE Moreover, adiponectin also decreased energy expenditure. Adiponectin-deficient mice showed decreased AMPK phosphorylation in the ARH, decreased food intake, and increased energy expenditure, exhibiting resistance to high-fat-diet-induced obesity. Serum and cerebrospinal fluid levels of Adiponectin (Clin. Chem. 53:1541, 2007) and expression of AdipoR1 in the ARH were increased during fasting and decreased after refeeding. We conclude that adiponectin stimulates food intake and decreases energy expenditure during fasting through its effects in the central nervous system (Cell Metab. 6:55, 2007; FEBS Lett. 582:74, 2008).

Research Products

• [Journal Article] Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. (2007)
  • Author(s): Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara
  • Journal Title: Nat Med. 13 Pages: 332-339
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Adiponectin stimulates AMP-activated protein kinase in the hypothalam us and increases food intake. (2007)
  • Author(s): Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y,
  • Journal Title: Cell Metab. 6 Pages: 55-68
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Improved ELISA for selective measurement of adiponectin multimers and identification of adiponectin in human cerebrospinal fluid. (2007)
  • Author(s): Ebinuma H, Miida T, Yamauchi T, Hada Y, Hara K, Kubota N, Kadowaki T.
  • Journal Title: Clin Chem. 53 Pages: 1541-1544
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Phenotypes of IRS-2 deficient mice produced by reproductive technology are stable. (2007)
  • Author(s): Hashimoto H, Arai T, Ohnishi Y, Eto T, Ito M, Hioki K, Suzuki R, Yamauchi T, Ohsugi M, Saito M, Ueyama Y, Tobe K, Kadowaki T, Tamaoki N, Kosaka K.
  • Journal Title: Exp Anim. 56 Pages: 149-154
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2. (2007)
  • Author(s): Ishikawa M, Kitayama J, Yamauchi T, Kadowaki T, Maki T, Miyato H, Yamashita H, Nagawa H.
  • Journal Title: Cancer Sci. 98 Pages: 1120-1127
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Targeted disruption ofAdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions (2007)
  • Author(s): Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T.
  • Journal Title: Nat Med. 13 Pages: 322-339
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake (2007)
  • Author(s): Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T.
  • Journal Title: Cell Metab 6 Pages: 55-68
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Improved ELISA for selective measurement of adiponectin multimers and identification of adiponectin in human cerebrospinal fluid (2007)
  • Author(s): Ebinuma H, Miida T, Yamauchi T, Hada Y, Hara K, Kubota N, Kadowaki T.
  • Journal Title: Clim Chem 53 Pages: 1541-1544
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Phenotypes of IRS-2 deficient mice produced by reproductive technology are stable (2007)
  • Author(s): Hashimoto H, Arai T, Ohnishi Y, Eto T, Ito M, Hioki K, Suzuki R, Yamauchi T, Ohsugi M, Saito M, Ueyama Y, Tobe K, Kadowaki T, Tamaoki N, Kosaka K.
  • Journal Title: Exp Anim 56 Pages: 149-154
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoRl and AdipoR2 (2007)
  • Author(s): Ishikawa M, Kitayama J, Yamauchi T, Kadowaki T, Maki T, Miyato H, Yamashita H, Nagawa H.
  • Journal Title: Cancer Sci. 98 Pages: 1120-1127
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pioglitazone Ameliorates Insulin Resistance and Diabetes by Both Adiponectin-dependent and -independent Pathways. (2006)
  • Author(s): Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Is hikawa M, Moroi M, Sugi K, Ya mauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T.
  • Journal Title: J. Biol. Chem. 281 Pages: 8748-8755
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Measurement of the high- molecular- weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. (2006)
  • Author(s): Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T.
  • Journal Title: Diabetes Care 29 Pages: 1357-1362
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Overexpression of MCP-1 in adipose tissues causes macrophage recruitment and insulin resistance. (2006)
  • Author(s): Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S, Manabe I, Hashimoto H, Ohnishi Y, ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Tsunoda M, Id
  • Journal Title: J. Bio1. Chem. 281 Pages: 26602-26614
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. (2006)
  • Author(s): Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K.
  • Journal Title: J. Clin. Invest. 116 Pages: 1784-1792
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Adiponectin-dependent and independent pathways in insulin-sensitizing and antidiabetic actions of thiazolidinediones. (2006)
  • Author(s): Kubota N, Yamauchi T, Tobe K, Kadowaki, T
  • Journal Title: Diabetes 55 Suppl 2 Pages: S32-38
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pioglitazone Ameliorates Insulin Resistance and Diabetes by-Both Adiponectin-dependent and-independent Pathways (2006)
  • Author(s): Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Ishikawa M, Moroi M, Sugi K, Yamauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T.
  • Journal Title: J. Biol. Chem 281 Pages: 8748-8755
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Measurement of the high-molecular-weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome (2006)
  • Author(s): Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T.
  • Journal Title: Diabetes Care 29 Pages: 1357-1362
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of MCP-1 in adipose tissues causes macrophage recruitment and insulin resistance (2006)
  • Author(s): Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S, Manabe I, Hashimoto H, Ohnishi Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Nagai R, Kadowaki T.
  • Journal Title: J. Biol. Chem 281 Pages: 26602-26614
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome (2006)
  • Author(s): Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K.
  • Journal Title: J. Clin. Invest 116 Pages: 1784-1792
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adiponectin-dependent and-independent pathways in insulin-sensitizing and antidiabetic actions of thiazolidinediones (2006)
  • Author(s): Kubota N, Yamauchi T, Tobe K, Kadowaki, T.
  • Journal Title: Diabetes 55 Pages: 32-38
  • Description: 「研究成果報告書概要(欧文)」より