Chan Chi Bun, Tse Margaret Chui Ling, Liu Xia, Zhang Shuai, Schmidt Robin, Otten Reed, Liu Liegang, Ye Keqiang
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA; Department of Physiology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Chem Biol. 2015 Mar 19;22(3):355-68. doi: 10.1016/j.chembiol.2015.02.003. Epub 2015 Mar 5.
Chronic activation of brain-derived neurotrophic factor (BDNF) receptor TrkB is a potential method to prevent development of obesity, but the short half-life and nonbioavailable nature of BDNF hampers validation of the hypothesis. We report here that activation of muscular TrkB by the BDNF mimetic, 7,8-dihydroxyflavone (7,8-DHF), is sufficient to protect the development of diet-induced obesity in female mice. Using in vitro and in vivo models, we found that 7,8-DHF treatment enhanced the expression of uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) activity in skeletal muscle, which resulted in increased systemic energy expenditure, reduced adiposity, and improved insulin sensitivity in female mice fed a high-fat diet. This antiobesity activity of 7,8-DHF is muscular TrkB-dependent as 7,8-DHF cannot mitigate diet-induced obesity in female muscle-specific TrkB knockout mice. Hence, our data reveal that chronic activation of muscular TrkB is useful in alleviating obesity and its complications.
脑源性神经营养因子（BDNF）受体TrkB的慢性激活是预防肥胖发生的一种潜在方法，但BDNF的半衰期短且无生物利用性阻碍了该假说的验证。我们在此报告，BDNF模拟物7,8-二羟基黄酮（7,8-DHF）对肌肉TrkB的激活足以保护雌性小鼠免受饮食诱导的肥胖。使用体外和体内模型，我们发现7,8-DHF处理可增强骨骼肌中解偶联蛋白1（UCP1）的表达和AMP激活的蛋白激酶（AMPK）活性，这导致高脂饮食喂养的雌性小鼠全身能量消耗增加、肥胖减轻且胰岛素敏感性提高。7,8-DHF的这种抗肥胖活性依赖于肌肉TrkB，因为7,8-DHF无法减轻雌性肌肉特异性TrkB基因敲除小鼠的饮食诱导肥胖。因此，我们的数据表明，肌肉TrkB的慢性激活有助于减轻肥胖及其并发症。
