Molecular mechanism of BDNF as a agent that circumvents leptin resistance

BDNF 作为规避瘦素抵抗剂的分子机制

• 批准号: 13557089
• 负责人: OGAWA Yoshihiro
• 金额: $ 8.77万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557089/
• 关键词: leptin 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

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.

在这项研究中，我们研究了脑源性神经营养因子（BDNF）是否作为一种抗肥胖和抗糖尿病的药物，可以绕过瘦素抵抗。我们证明BDNF在两种不同的瘦素抵抗模型中有效；通过高脂饮食4个月致肥胖的获得性C57BL/6J模型小鼠（饮食性肥胖小鼠（DIO））和致死性黄刺鼠（KKA^y小鼠）遗传模型小鼠。腹腔注射BDNF （10 mg/kg × 2）可显著减少DIO小鼠24 h内的累积进食量，而对腹腔注射瘦素（10 mg/kg × 2）无反应。BDNF对标准饮食小鼠的抗肥胖作用不明显。在24岁以上的小鼠中，IP注射重组瘦素导致小鼠累积食物摄取量显著减少。接下来，我们研究了重复给药BDNF （10 mg/kg/天，连续6天）对DIO小鼠的影响，并在最后一次给药后进行口服葡萄糖耐量试验（OGTT）。OGTT期间，bdnf处理的DIO小鼠血糖曲线下面积（AUC）显著低于对照组（P < 0.01）。我们还观察到BDNF对KKA^y小鼠的肥胖和糖尿病有改善作用。最近，我们在肝脏特异性血清淀粉样蛋白P组分P启动子的控制下生产了过表达BDNF的转基因小鼠，并发现当喂食标准或高脂肪饮食时，它们的食物摄入量和体重相对于非转基因幼崽都有所减少。总的来说，这些观察结果表明BDNF可能用于治疗瘦素抵抗性肥胖和糖尿病。

项目成果

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M.Shintani 等人：“Ghrelin 是一种内源性生长激素促分泌素，是一种新型的食欲肽，通过激活下丘脑神经肽 Y/Y1 受体途径来拮抗瘦素作用”。

H.Chusho et al.: "Dwarfism and early death in mice lacking C-type natriuretic Peptide"Proc. Natl. Acad. Sci. USA. 98. 4016-4021 (2001)

H.Chusho 等人：“缺乏 C 型利尿钠肽的小鼠的侏儒症和早期死亡”Proc。

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)

T.Nakakawa 等人：“脑源性神经营养因子在瘦素抵抗啮齿动物模型中的抗肥胖和抗糖尿病作用”Int。

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)

T.Nakakawa 等人：“脑源性神经营养因子在瘦素抵抗啮齿动物模型中的抗肥胖和抗糖尿病作用”Int。

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)

Y.Okawa 等人：“瘦素在生活方式相关疾病中的病理生理作用：过度表达瘦素的转基因瘦小鼠的研究”J.