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

作者：Andrews Zane B; Liu Zhong Wu; Walllingford Nicholas; Erion Derek M; Borok Erzsebet; Friedman Jeffery M; Tschop Matthias H; Shanabrough Marya; Cline Gary; Shulman Gerald I; Coppola Anna; Gao Xiao Bing; Horvath Tamas L^*; Diano Sabrina

来源：Nature, 2008, 454(7206): 846-851.

DOI：10.1038/nature07181

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.

• 出版日期2008-8-14