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

基本信息

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

项目摘要

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) 是否可以作为抗肥胖和抗糖尿病药物来规避瘦素抵抗，我们证明 BDNF 在两种不同的瘦素抵抗模型或 C57BL/ 中有效。 6J 小鼠通过摄入高脂肪饮食 4 个月而变得肥胖（饮食诱导肥胖（DIO）小鼠）和遗传模型或致死性黄色刺豚鼠（KKA^y 小鼠）。腹膜内（IP）施用BDNF（10 mg/kg × 2）显着减少DIO小鼠24小时内的累积食物摄入量，而它们对IP施用瘦素（10 mg/kg × 2）没有反应。 BDNF的抗肥胖作用。在喂食标准饮食的小鼠中，IP 注射重组瘦素导致 24 岁以上喂食标准饮食的小鼠的累积食物摄入量显着减少。接下来我们检查了重复注射的效果。对DIO小鼠给予BDNF（10mg/kg/天，持续6天），并在末次给药后进行口服葡萄糖耐量试验（OGTT），BDNF处理的DIO小鼠的血糖曲线下面积（AUC）显着增加。 OGTT 期间的 BDNF 低于媒介物处理的 DIO 小鼠（P < 0.01）。我们还观察到 BDNF 可有效改善 KKA^y 小鼠的肥胖和糖尿病。最近，我们培育了过度表达 BDNF 的转基因小鼠。在肝脏特异性血清淀粉样蛋白 P 成分 P 启动子的控制下，发现当喂食标准或高脂肪饮食时，它们表现出相对于非转基因同窝动物的食物摄入量和体重减少。总的来说，这些观察结果表明 BDNF 可能具有治疗作用。用于治疗瘦素抵抗性肥胖和糖尿病。