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The therapeutic application of lipolytic machinery to obesity and its related disorders

Research Project

Project/Area Number 15590930
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionThe University of Tokyo

Principal Investigator

OSUGA Jun-ichi  The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (10334400)

Co-Investigator(Kenkyū-buntansha) OHASHI Ken  The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (40376463)
YAHAGI Naoya  The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
TAMURA Yoshiaki  The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
OKAZAKI Hiroaki  The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
Keywordslipase / adipocyte / obesity / ホルモン感受性リパーゼ / トリグリセリド
Research Abstract

Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol (TG) and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep^<ob/ob>/HSL^<-1->) by crossbreeding HSL^<-/-> mice with genetically obese Lep^<ob/ob> mice. Unexpectedly, Lep^<ob/ob>/HSL^<-/-> mice ate less food, gained less weight and had lower adiposity than Lep^<ob/ob>/HSL^<+/+> mice. Lep^<ob/ob>/HSL^<-/-> mice had massive accumulation of preadipocytes in white adipose tissues (WAT) with increased expression of preadipocyte-specific genes (C/EBPβ and ADRP) and decreased expression of genes characteristic of mature adipocytes (C/EBPα, PPARγ and ADD-1/SREBP-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (22 results)

All 2004 2003 Other

All Journal Article (17 results) Publications (5 results)

  • [Journal Article] Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice.2004

    • Author(s)
      Sekiya M
    • Journal Title

      J Biol Chem 279

      Pages: 15084-15090

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] p53 involvement in the pathogenesis of fatty liver disease.2004

    • Author(s)
      Yahagi N
    • Journal Title

      J Biol Chem 279

      Pages: 20571-20575

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetvlated low density lipoproteins by macrophages stimulated with lipopolysaccharide.2004

    • Author(s)
      Tamura Y
    • Journal Title

      J Biol Chem 279

      Pages: 30938-30944

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice.2004

    • Author(s)
      Sekiya M, Osuga J, Okazaki H, Yahagi N, Harada K, Shen WJ, Tamura Y, Tomita S, Iizuka Y, Ohashi K, Okazaki M, Sata M, Nagai R, Fujita T, Shimano H, Kraemer FB, Yamada N, Ishibashi S.
    • Journal Title

      J Biol Chem 279

      Pages: 15084-15090

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] p53 involvement in the pathogenesis of fatty liver disease.2004

    • Author(s)
      Yahagi N, Shimano H, Matsuzaka T, Sekiya M, Najima Y, Okazaki S, Okazaki H, Tamura Y, Iizuka Y, Inoue N, Nakagawa Y, Takeuchi Y, Ohashi K, Harada K, Gotoda T, Nagai R, Kadowaki T, Ishibashi S, Osuga J, Yamada N.
    • Journal Title

      J Biol Chem 279

      Pages: 20571-20575

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetylated low density lipoproteins by macrophages stimulated with lipopolysaccharide.2004

    • Author(s)
      Tamura Y, Osuga J, Adachi H, Tozawa R, Takanezawa Y, Ohashi K, Yahagi N, Sekiya M, Okazaki H, Tomita S, Iizuka Y, Koizumi H, Inaba T, Yagyu H, Kamada N, Suzuki H, Shimano H, Kadowaki T, Tsujimoto M, Arai H, Yamada N, Ishibashi S.
    • Journal Title

      J Biol Chem 279

      Pages: 30938-30944

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice.2004

    • Author(s)
      Sskiya M
    • Journal Title

      J Biol Chem 279(15)

      Pages: 15084-15090

    • Related Report
      2004 Annual Research Report
  • [Journal Article] p53 involvement in the pathogenesis of fatty liver disease.2004

    • Author(s)
      Yahagi N
    • Journal Title

      J Biol Chem 279(20)

      Pages: 20571-20575

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Scavenger receptor expressed by endothelial cells I(SREC-I)mediates the uptake of acetylated low density lipoproteins by macrophagea stimulated with lipopolysaccharide.2004

    • Author(s)
      Tamura Y
    • Journal Title

      J Biol Chem 279(30)

      Pages: 30938-30944

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice.2004

    • Author(s)
      Matsuzaka T
    • Journal Title

      Diabetes 53(3)

      Pages: 560-569

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hormone-sensitive lipase is required for high-density lipoprote in cholesteryl ester-supported adrenal steroidogenesis.2004

    • Author(s)
      Kraemer FB
    • Journal Title

      Mol Endocrinol 18(3)

      Pages: 549-557

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice.2003

    • Author(s)
      Harada K
    • Journal Title

      Am J Physiol Endocrinol Metab 285

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene.2003

    • Author(s)
      Ohashi K
    • Journal Title

      J Biol Chem 278

      Pages: 42936-42941

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression.2003

    • Author(s)
      Sekiya M
    • Journal Title

      Hepatology 38

      Pages: 1529-1539

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice.2003

    • Author(s)
      Harada K, Shen WJ, Patel S, Natu V, Wang J, Osuga J, Ishibashi S, Kraemer FB.
    • Journal Title

      Am J Physiol Endocrinol Metab 285

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene.2003

    • Author(s)
      Ohashi K, Osuga J, Tozawa R, Kitamine T, Yagyu H, Sekiya M, Tomita S, Okazaki H, Tamura Y, Yahagi N, Iizuka Y, Harada K, Gotoda T, Shimano H, Yamada N, Ishibashi S.
    • Journal Title

      J Biol Chem 278

      Pages: 42936-42941

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression.2003

    • Author(s)
      Sekiya M, Yahagi N, Matsuzaka T, Najima Y, Nakakuki M, Nagai R, Ishibashi S, Osuga J, Yamada N, Shimano H.
    • Journal Title

      Hepatology 38

      Pages: 1529-1539

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Tamura, Yoshiaki: "FEEL-1 and FEEL-2 are endocytic receptors for advanced glycation end products."J Biol Chem. 278(15). 12613-12617 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yahagi, Naoya: "p53 Activation in adipocytes of obese mice."J Biol Chem. 278(28). 25395-25400 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ohashi, Ken: "Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene."J Biol Chem. 278(44). 42936-42941 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Harada, Kenji: "Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice."Am J Physiol Endocrinol Metab. 285(6). E1182-E1195 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sekiya, Motohiro: "Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lepob/ob mice."J Biol Chem. (in press). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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