Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin
Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin
复制标题
DOI：
10.1016/j.cmet.2008.03.006
复制
发表时间：
2008-05-01
期刊：
影响因子：
29
通讯作者：
Vidal-Puig, Antonio
中科院分区：
文献类型：
--
作者：
Lopez, Miguel;Lage, Ricardo;Vidal-Puig, Antonio
目前的证据表明，下丘脑脂肪酸代谢可能在调节食物摄入量方面发挥作用；然而，确认下丘脑脂肪酸代谢是与生理相关的进食调节系统仍不完整。在这里，我们使用药理学和遗传学的方法来证明对Ghrelin的生理性食欲反应涉及到由AMPK诱导的脂肪酸生物合成的特异性抑制，从而导致下丘脑丙二酰辅酶A水平下降和肉碱棕榈酰转移酶1(CPT1)活性增加。此外，我们还证明了禁食以一种区域特异性的方式下调脂肪酸合成酶(Fas)，并且这种影响是由AMPK和Ghrelin依赖的机制介导的。因此，降低下丘脑腹内侧核(VMH)的AMPK活性足以抑制Ghrelin对Fas表达和摄食的影响。总体而言，我们的结果表明，下丘脑脂肪酸代谢的调节特别是VMH对Ghrelin的反应是控制摄食的一种生理机制。
Current evidence suggests that hypothalamic fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic response to ghrelin involves specific inhibition of fatty acid biosynthesis induced by AMP-activated protein kinase (AMPK) resulting in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. In addition, we also demonstrate that fasting downregulates fatty acid synthase (FAS) in a region-specific manner and that this effect is mediated by an AMPK and ghrelin-dependent mechanisms. Thus, decreasing AMPK activity in the ventromedial nucleus of the hypothalamus (VMH) is sufficient to inhibit ghrelin's effects on FAS expression and feeding. Overall, our results indicate that modulation of hypothalamic fatty acid metabolism specifically in the VMH in response to ghrelin is a physiological mechanism that controls feeding.