Brain fatty acid synthase activates PPARα to maintain energy homeostasis
Brain fatty acid synthase activates PPARα to maintain energy homeostasis
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DOI：
10.1172/jci31183
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Semenkovich, Clay F.
中科院分区：
文献类型：
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作者：
Chakravarthy, Manu V.;Zhu, Yimin;Semenkovich, Clay F.
中枢神经系统对能量平衡的控制影响肥胖和糖尿病的易感性，但脂肪酸、丙二酰辅酶A和其他代谢物如何在该部位作用以改变代谢尚不清楚。脂肪酸合成酶（FAS）的药理学抑制，从头脂肪生成的速率限制，独立于瘦素降低食欲，但也通过与FAS抑制无关的活动促进体重减轻。在这里，我们报告了FAS在胰腺β细胞和下丘脑中的条件性通用失活产生了瘦的、低食欲的小鼠，其具有增加的体力活动和受损的下丘脑PPAR α信号传导。给予下丘脑的PPAR α激动剂增加了PPAR α靶基因和正常化的食物摄入。β细胞FAS酶活性的失活对培养或体内胰岛功能没有影响。这些结果表明，大脑FAS不仅在调节摄食，而且在调节身体活动中起关键作用，这些作用似乎是通过提供FAS产生的配体介导的。因此，有2种截然相反的蛋白质，FAS（由进食诱导）和PPAR α。（由饥饿诱导），意外地在中枢神经系统中形成一个综合感觉模块，以协调能量平衡。
Central nervous system control of energy balance affects susceptibility to obesity and diabetes, but how fatty acids, malonyl-CoA, and other metabolites act at this site to alter metabolism is poorly understood. Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition. Here we report that the conditional generic inactivation of FAS in pancreatic beta cells and hypothalamus produced lean, hypophagic mice with increased physical activity and impaired hypothalamic PPAR alpha signaling. Administration of a PPAR alpha agonist into the hypothalamus increased PPAR alpha target genes and normalized food intake. Inactivation of beta cell FAS enzyme activity had no effect on islet function in culture or in vivo. These results suggest a critical role for brain FAS in the regulation of not only feeding, but also physical activity, effects that appear to be mediated through the provision of ligands generated by FAS to PPAR alpha. Thus, 2 diametrically opposed proteins, FAS (induced by feeding) and PPAR alpha. (induced by starvation), unexpectedly form an integrative sensory module in the central nervous system to orchestrate energy balance.