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由胃分泌的激素Ghrelin,Ghrelin 是1999年由日本科学家Kojima最先在小鼠和人胃内分泌细胞中发现的含有28个氨基酸的脑肠肽.Ghrelin主要由胃分泌,下丘脑、肾脏、胎盘等 也有分泌.Ghrelin mRNA的表达部位十分广泛,细胞密集分布于胃部泌酸腺的颈部至底部.最近又在人的下丘脑和脑干发现Ghrelin的特异性受体--促生长激素分泌受体. 具有刺激生长激素释放、调节机体生长发育、增加食欲、调节能量平衡的作用,同时有健进胃酸的分泌功能,并且与机体肥胖和癌症有关。通过调控下丘脑弓状核中的NPY/AgRP神经元来刺激食物吸收。它是怎样做到这一点的过去并不清楚,但现在用小鼠所做研 究表明,由Ghrelin诱导的食欲增强是由在下丘脑线粒体中燃烧脂肪驱动,该线粒体能产生被线粒体蛋白UCP2(去耦合蛋白2)利用的自由基。这便提 出一个可能性:自由基参与了食欲调控,能够影响自由基的干涉也许能够影响食欲及吃饱的感觉。
Nature 454, 846-851 (14 August 2008) | doi:10.1038/nature07181 UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals Zane B. Andrews1,2, Zhong-Wu Liu2,5, Nicholas Walllingford2, Derek M. Erion2, Erzsebet Borok2, Jeffery M. Friedman6, Matthias H. Tschöp7, Marya Shanabrough2, Gary Cline3, Gerald I. Shulman3, Anna Coppola2, Xiao-Bing Gao2, Tamas L. Horvath1,2,4 & Sabrina Diano2,4
Correspondence to: Tamas L. Horvath1,2,4Sabrina Diano2,4 Correspondence and requests for materials should be addressed to T.L.H. (Email: tamas.horvath@yale.edu) or S.D. (Email: sabrina.diano@yale.edu).
AbstractThe gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.
最后修改于 2008-08-25 13:55
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