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

Research Project

Project/Area Number 18390270
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionThe 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 *help
¥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)
Keywordsdiabetes / 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 … More 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). Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (44 results)

All 2008 2007 2006

All Journal Article (31 results) (of which Peer Reviewed: 15 results) Presentation (5 results) Book (8 results)

  • [Journal Article] The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS2008

    • Author(s)
      Kadowaki T, Yamauchi T, Kuhota N.
    • Journal Title

      FEBS Lett 582

      Pages: 74-80

    • Related Report
      2007 Annual Research Report
    • 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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Targeted disruption of AdipoRl and AdipoR2 causes abrogation of adiponectin binding and metabolic actions2007

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake2007

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Improved ELISA for selective measurement of adiponectin multimers and identification of adiponectin in human cerebrospinal fluid2007

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Phenotypes of IRS-2 deficient mice produced by reproductive technology are stable2007

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR22007

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Adiponectin stmulates AMP-activated protein kinase in the hypothalam us and increases food intake2007

    • 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

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Improved EHSA for selective measurement of adiponectin multimers and identification of adiponectin in human cerebrospinal fluid2007

    • Author(s)
      Ebinuma H, Miida T, Yamauchi T, Hada Y, Hara K, Kubota N, Kadowaki T.
    • Journal Title

      Clin Chem 53

      Pages: 1541-1544

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phenotypes of IRS-2 deficient mice produced by reproductive technology are stable2007

    • 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

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specfic membrane receptors Adipol and AdipoR22007

    • 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

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2006 Annual Research Report
  • [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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • 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
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Pioglitazone Ameliorates Insulin Resistance and Diabetes by Both Adiponectin-dependent and -independent Pathways2006

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Measurement of the high- molecular- weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome2006

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Overexpression of MCP-1 in adipose tissues causes macrophage recruitment and insulin resistance2006

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome2006

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Adiponectin-dependent and -independent pathways in insulin-sensitizing and antidiabetic actions of thiazolidinediones2006

    • 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
    • Related Report
      2007 Final Research Report Summary
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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

    • Related Report
      2006 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report
  • [Presentation] アディポネクチン受容体の生理的・病態生理的意義の解明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
    • Related Report
      2007 Annual Research Report
  • [Presentation] Pathophysiological roles of Adiponectin and Adiponectin Receptors2007

    • 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
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report
  • [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

    • Author(s)
      山内 敏正、門脇 孝
    • Publisher
      最新医学
    • Related Report
      2007 Annual Research Report
  • [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

    • Author(s)
      山内 敏正、門脇 孝
    • Publisher
      最新医学社
    • Related Report
      2007 Annual Research Report
  • [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

    • Author(s)
      山内 敏正、門脇 孝
    • Publisher
      BIO Clinica
    • Related Report
      2007 Annual Research Report
  • [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

    • Author(s)
      山内 敏正、原一 雄、門脇 孝
    • Publisher
      日本医師会雑誌
    • Related Report
      2007 Annual Research Report
  • [Book] オスモチン2007

    • Author(s)
      山内 敏正、門脇 孝
    • Publisher
      臨床栄養
    • Related Report
      2007 Annual Research Report
  • [Book] アディポネクチンの臨床応用の現状・展望(Q&A)2007

    • Author(s)
      山内 敏正、門脇 孝
    • Publisher
      日本医事新報
    • Related Report
      2007 Annual Research Report
  • [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

    • Author(s)
      山内 敏正、門脇 孝
    • Publisher
      日本臨牀
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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