Identification of transcription factor which regulates obesity-linked downregulation of adiponectin gene and development of treatment modality for metabolic syndrome

• Project/Area Number: 18390270
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: YAMAUCHI Toshimasa The University of Tokyo, Faculty of Medicine, Project Associate Professor (40372370)
• Co-Investigator(Kenkyū-buntansha): KUBOTA Naoto The University of Tokyo, Faculty of Medicine, Project Associate Professor (50396719) ; HARA Kazuo The University of Tokyo, Faculty of Medicine, Lecturer (50359600) ; KADOWAKI Takashi The University of Tokyo, Faculty of Medicine, Professor (30185889)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥17,750,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
• Keywords: diabetes / adipokine / promoter

Research Abstract

To clarify the mechanism by which obesity results in downregulation of Adiponectin (Ad) gene, we first tried to identify the promoter region of the Ad gene that confers the response to obesity and its responsible transcription factor(s) by using a combination of functional promoter studies and electrophoretic mobility shift assays (EMSAs) techniques in hypertrophic adipocytes model in vitro. We identified one such promoter region, which we named Diabetes/obesity-Related Element (DRE), and its binding protein(s) (Dre binding protein; Deb). Deb1 gene turned out to be a KLF family transcription factor by yeast one-hybrid screen.
EMSAs and chromatin immunoprecipitation assays revealed that Deb1 indeed bound to DRE. Deb1 dose-dependently and specifically enhanced Ad promoter activity. Regulation of Ad transcription by Deb1 was confirmed by corresponding changes in endogenous Ad mRNA by Deb1 siRNA and Deb1 overexpression in vitro. Targeted disruption of Deb1 caused a partial but significant r eduction of Ad expression in WAT and plasma Ad levels. Interestingly, expression of Deb1 and its binding to DRE were reduced in obese mice such as ob/ob mice. Moreover, we found that increased oxidative stress and inflammation as well as changes in hormonal receptor signalling observed within hypertrophic adipocytes reduced Deb1 and Ad, and that normalization of these intracellular alterations increased Deb1 and Ad.
Taken together, these results suggested that 1) obesity decreases Deb1 via multiple pathways such as oxidative stress and inflammation, which leads to Ad reduction, 2) Deb1 activators in WAT may provide a novel treatment modality for metabolic syndrome (manuscript in preparation).
Moreover, we showed that not only plasma adiponectin levels but also expression levels of AdipoR1/R2 were decreased in obesity, which appeared to play causal roles in the development of insulin resistance. Furthermore, we showed that not only agonism of AdipoR1/R2 but also strategies to increase AdipoR1/R2 in the presence of adiponectin indeed resulted in amelioration of insulin resistance and type 2 diabetes (Nat. Med. 13:332,2007).

Research Products

• [Journal Article] The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS (2008)
  • Author(s): Kadowaki T, Yamauchi T, Kuhota N.
  • Journal Title: FEBS Lett 582 Pages: 74-80
  • Peer Reviewed
• [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 K,Tobe K,Nagai R,Ueki K,Kadowaki T.
  • 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 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(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
  • NAID: 130000068045
  • 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 of AdipoRl 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: 332-339
  • 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: Clin 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
  • NAID: 130000068045
  • 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 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(欧文)」より
• [Journal Article] Adiponectin stmulates 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,Kadowaki T.
  • Journal Title: Cell Metab 6 Pages: 55-68
  • Peer Reviewed
• [Journal Article] Improved EHSA 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
  • 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
  • NAID: 130000068045
  • Peer Reviewed
• [Journal Article] Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specfic membrane receptors Adipol 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
  • Peer Reviewed
• [Journal Article] Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. (2007)
  • Author(s): Yamauchi T, Kubota N, Kadowaki T.
  • Journal Title: Nature Medicine 13(3) Pages: 332-339
• [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, lshikawa 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(和文)」より
  • Peer Reviewed
• [Journal Article] Measurement of the high-molecular-weight form of adiponectin in plasmais useful for the prediction of insulih 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, Nagai R, Kadowaki T.
  • Journal Title: J.Biol. 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 Suppl2
  • 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
  • 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, Yamauchi T, Kadowaki T.
  • Journal Title: J. Biol. Chem. 281 Pages: 8748-8755
• [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 T, Yamauchi T, Kadowaki T.
  • Journal Title: Diabetes Care 29 Pages: 1357-1362
• [Journal Article] Overexpression of MCP-1 in adipose tissues causes macrophage recruitment and insulin resistance. (2006)
  • Author(s): ・Kubota N, Yamauchi T, Kadowaki T.
  • Journal Title: J. Biol. Chem. 281 Pages: 26602-26614
• [Journal Article] Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. (2006)
  • Author(s): Kadowaki T, Yamauchi T, Kubota N, et al.
  • Journal Title: J. Clin. Invest. 116 Pages: 1784-1792
• [Journal Article] Adiponectin-dependent and -independent pathways in insulin-sensitizing and antidiabetic actions of thiazolidinediones. (2006)
  • Author(s): Kubota N, Yamauchi T, ・Kadowaki T.
  • Journal Title: Diabetes 55 Suppl 2
• [Presentation] メタボリックシンドロームアディポネクチン/AdipoRの病態生理的意義 (2007)
  • Author(s): 山内 敏正, 原一 雄, 窪田 直人, 植木浩 二郎, 戸辺 一之, 門脇 孝
  • Organizer: 第44回日本臨床分子医学会学術総会
  • Place of Presentation: 和歌山
  • Year and Date: 2007-07-20
• [Presentation] シンポジウム「アディポネクチン・アディポネクチン受容体の生理的・病態生理的意義」 (2007)
  • Author(s): 山内 敏正
  • Organizer: 第50回日本糖尿病学会年次学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2007-05-25
• [Presentation] Pathophysiological roles of Adiponectin and Adiponectin Receptors (2007)
  • Author(s): Toshmasa Yamauchi, Naoto Kubota, Kazuo Hara, Kohjio Ueki, Kazuyuki Tobe and Takashi Kadowaki
  • Organizer: Okazaki Symposium 2007 on Obesity & Diabetes
  • Place of Presentation: Okazaki
  • Year and Date: 2007-04-14
• [Presentation] メタボリックシンドローム-その分子病態- (2007)
  • Author(s): 山内 敏正
  • Organizer: 第27回日本医学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2007-04-07
• [Book] 【糖尿病の新しい治療戦略】糖尿病の治療戦略インスリン抵抗性改善薬の現状と未来 (2007)
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  • Publisher: 最新医学
• [Book] 特集糖尿病の新しい治療戦略インスリン抵抗性改善薬の現状と未来 (2007)
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  • Publisher: 最新医学社
• [Book] 【糖尿病による心血管合併症】インスリン抵抗性と動脈硬化症 (2007)
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  • Publisher: BIO Clinica
• [Book] 【メタボリックシンドロームup to date】検査・診断アディポネクチン (2007)
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• [Book] オスモチン (2007)
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  • Publisher: 臨床栄養
• [Book] アディポネクチンの臨床応用の現状・展望(Q&A) (2007)
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  • Publisher: 日本医事新報
• [Book] 脂質代議常-高脂血症・低脂血症-I概論高脂血症と動脈硬化動脈硬化発症にかかわるアディポサイトカインの役割 (2007)
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• [Book] アディポサイトカイン調節を改善する食事療法 (2007)
  • Author(s): 山内 敏正、門脇 孝
  • Publisher: Adiposcience