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Molecular mechanism of leptin-induced increase in glucose and lipid metabolism

Research Project

Project/Area Number 13470225
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

OGAWA Yoshihiro  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (70291424)

Co-Investigator(Kenkyū-buntansha) INOUE Gen  Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 講師 (20260606)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2002: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2001: ¥8,200,000 (Direct Cost: ¥8,200,000)
Keywordsleptin / lipoatrophic diabetes / adrenoceptor / microarray / fatty acid / respiration / マイクロアレイ法 / トランスジェニックマウス / 脂肪酸合成 / 脂肪酸酸化 / 肝臓 / 糖代謝 / 脂質代謝 / A-ZIPTgマウス / 塩酸ブナゾジン
Research Abstract

We have demonstrated that transgenic overexpression of leptin can rescue the insulin-resistant diabetes and hepatic steatosis in a mouse model of lipoatrophic diabetes (A-ZIPTg mice), suggesting the potential usefulness of leptin as an antidiabetic agent. However, the molecular mechanisms underlying the leptin-induced increase in glucose and lipid metabolism is not clear. In this study, we examined the effect of sympathetic blockade on the leptin-induced increase in glucose metabolism in LepTg/A-ZIPTg mice obtained through genetic cross between transgenic skinny mice overexpressing letpin (LepTg) and A-ZIPTg mice. We also characterized the profile of hepatic gene expression in LepTg/A-ZIPTg mice using cDNA microarray analysis. Intraperitoenal injection of α-adrenoceptor blocker (bunazasin) did not affect the improved glucose metabolism in LepTg/A-ZIPTg mice. However, β-adrenoceptor blocker (propranolol) did aggravate the glucose metabolism in the animals. Those observations suggest the involvement of β-adrenoceptor activation in the lepitn's antidiabetic effect.
Microarray analysis showed the upregulation in mRNAs encoding genes involved in glycolysis, respiratory chain, and insulin signal transduction in the liver from LepTg. By contrast, the expression of a wide variety of genes involved in fatty acid synthesis and oxidation programs was increased in A-ZIPTg mice. However, transgenic overexpression of leptin restored the expression of a large subset of genes, which are altered in A-ZIPTg mice, in LepTg/A-ZIPTg mice. Exogenous administration of leptin that elevates plasma leptin concentrations to those of LepTg/A-ZIPTg mice also resulted in the normalization of hepatic expressions of these genes in A-ZIPTg mice. These observations suggest that leptin alters hepatic gene expression in lipoatrophic diabetes, which leads to a change in energy metabolism from glucose utilization and fatty acid synthesis to fatty acid oxidation and increased respiration.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] N.Matsuoka et al.: "Decreased triglyceride-rich lipoproteins in transgenic skinny mice overexpressing leptin"Am. J. Physiol. 280. E334-E339 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Ebihara et al.: "Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes"Diabetes. 50. 1440-1448 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Kobayashi et al.: "A novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity"Diabetes. 51. 243-246 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Ogawa et al.: "Pathophysiogical role of leptin in lifestyle-related diseases : studies with transgenic skinny mice overexpressing leptin"J. Diabetes Complications. 16. 119-122 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T.Nakagawa et al.: "Antiobesity and antidiabetic effects of brain-derived neurotrophic factor in rodent models of leptin resistance"Int. J. Obes.. 27. 557-565 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] N. Matsuoka et al.: "Decreased triglyceride-rich lipoproteins in transgenic skinny mice overexpressing leptin"Am. J. Physiol. 280. E334-E339 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K. Ebihara et al.: "Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes"Diabetes. 50. 1440-1448 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H. Kobayashi et al.: "A novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity"Diabetes. 51. 243-246 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y. Ogawa et al.: "Pathophysiogical role of leptin in lifestyle-related diseases: studies with transgenic skinny miceoverexpressing leptin"J. Diabetes Complications. 16. 119-122 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T. Nakagawa et al.: "Antiobesity and antidiabetic effects of brain-derived neur otrophic factor in rodent models of leptin resistance"Int. J. Obes.. 27. 557-565 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Kobayashi et al.: "A novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity"Diabetes. 51. 243-246 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Ogawa et al.: "Pathophysiogical role of leptin in lifestyle-related diseases : studies with transgenic skinny mice overexpressing leptin"J. Diabetes Complications. 16. 119-122 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Shimizu et al.: "Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome"Thorax. 57. 429-434 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Ariyasu et al.: "Delayed short-term secretory regulation of ghrelin in obese animals : Evidenced by a specific radioimmunoassay for active form of ghrelin"Endocrinology. 143. 334-3350 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Miyawaki et al.: "Clinical implications of leptin and its potential humoral regulators in long-term low-calorie diet therapy for obese humans"Eur. J. Clin. Nutr.. 56. 593-600 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Nakagawa et al.: "Antiobesity and antidiabetic effects of brain-derived neurotrophic factor in rodent models of leptin resistance"Int. J. Obes.. in press. (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Shintani et al.: "Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway"Diabetes. 50. 227-232 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] N.Matsuoka et al.: "Decreased triglyceride-rich lipoproteins in transgenic skinny mice overexpressing leptin"Am. J. Physiol. 280. E334-E339 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Chusho et al.: "Dwarfism and early death in mice lacking C-type natriuretic peptide"Proc. Natl. Acad. Sci. USA. 98. 4016-4021 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Ebihara et al.: "Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes"Diabetes. 50. 1440-1448 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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