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

Zane B. Andrews, Zhong Wu Liu, Nicholas Walllingford, Derek M. Erion, Erzsebet Borok, Jeffery M. Friedman, Matthias H. Tschöp, Marya Shanabrough, Gary Cline, Gerald I. Shulman, Anna Coppola, Xiao Bing Gao, Tamas L. Horvath, Sabrina Diano

Research output: Contribution to journalArticlepeer-review

595 Scopus citations

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.

Original languageEnglish
Pages (from-to)846-851
Number of pages6
JournalNature
Volume454
Issue number7206
DOIs
StatePublished - 14 Aug 2008
Externally publishedYes

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