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Molecular mechanism of BDNF as a agent that circumvents leptin resistance

Research Project

Project/Area Number 13557089
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Endocrinology
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) TAIJI Mutsuo  Sumitomo Pharmaceuticals, Research Scientist, 創薬第二研究所, 主任研究員
HOSODA Kiminori  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (40271598)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2002: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2001: ¥8,200,000 (Direct Cost: ¥8,200,000)
Keywordsleptin resistance / BDNF / obesity / diabetes / DIO mice / KKA^y mice / transgenic mice / KKA^yマウス / 高脂肪食負荷 / レプチン
Research Abstract

In this study, we investigated whether or not brain-derived neurotrophic factor (BDNF) acts as an antiobesity and antidiabetic agent that can circumvent leptin resistance. We demonstrated that BDNF is effective in two different models of leptin resistance; an acquired model or C57BL/6J mice rendered obese by consumption of high-fat diet for 4 months (diet-induced obesity (DIO) mice) and a genetic model or lethal yellow agouti mice (KKA^y mice). Intraperitoneal (IP) administration of BDNF (10 mg/kg × 2) reduced significantly cumulative food intake of DIO mice over 24 h, whereas they were unresponsive to IP administration of leptin (10 mg/kg × 2). The antiobesity effect of BDNF was marginal in mice fed standard diet. IP injection of recombinant leptin caused a marked reduction of cumulative food intake in mice fed standard diet over 24. We next examined the effect of repetitive administration of BDNF (10 mg/kg/day for 6 days) in DIO mice and oral glucose tolerance test (OGTT) was conducted after the last administration. The area under curve (AUC) of blood glucose of BDNF-treated DIO mice was significantly lower than vehicle-treated DIO mice during OGTT (P < 0.01). We also observed that BDNF is effective in improving obesity and diabetes of KKA^y mice. Very recently, we have produced transgenic mice overexpressing BDNF under the control of the liver-specific serum amyloid P component P promoter and found that they exhibit reduced food intake and body weight relative to nontransgenic littermates, when fed either standard or high-fat diet. Collectively, these observations suggest that BDNF may be therapeutically used in the treatment of leptin-resistant obesity and diabetes.

Report

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

    (16 results)

All Other

All Publications (16 results)

  • [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)

    • 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] 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)

    • 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 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(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. 3341-3350 (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] 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

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

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