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Nature. 2008 Aug 14;454(7206):846-51. doi: 10.1038/nature07181. Epub 2008 Jul 30.

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

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  • 1Section of Comparative Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Howard Hughes Medical Institute, New York, New York 10021, USA.

Abstract

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.

PMID:
18668043
[PubMed - indexed for MEDLINE]
PMCID:
PMC4101536
Free PMC Article
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