UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals

被引：576

作者：

Andrews, Zane B. ^{[1
,2
]}

Liu, Zhong-Wu ^{[2
,5
]}

Walllingford, Nicholas ^{[2
]}

Erion, Derek M. ^{[2
]}

Borok, Erzsebet ^{[2
]}

Friedman, Jeffery M. ^{[6
]}

Tschop, Matthias H. ^{[7
]}

Shanabrough, Marya ^{[2
]}

Cline, Gary ^{[3
]}

Shulman, Gerald I. ^{[3
]}

Coppola, Anna ^{[2
]}

Gao, Xiao-Bing ^{[2
]}

Horvath, Tamas L. ^{[1
,2
,4
]}

Diano, Sabrina ^{[2
,4
]}

机构：

[1] Yale Univ, Sch Med, Comparat Med Sect, Howard Hughes Med Inst, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA

[3] Yale Univ, Sch Med, Dept Internal Med, Howard Hughes Med Inst, New Haven, CT 06520 USA

[4] Yale Univ, Sch Med, Dept Neurobiol, Howard Hughes Med Inst, New Haven, CT 06520 USA

[5] Yunyang Med Coll, Dept Neurobiol, Shiyan 442000, Hubei, Peoples R China

[6] Rockefeller Univ, Genet Mol Lab, Howard Hughes Med Inst, New York, NY 10021 USA

[7] Univ Cincinnati, Dept Psychiat, Cincinnati, OH 45237 USA

来源：

NATURE | 2008年 / 454卷 / 7206期

关键词：

D O I：

10.1038/nature07181

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The 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.

引用

页码：846 / 851

页数：6

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