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 () and Sabrina Diano ()
Additional contact information
Zane B. Andrews: Section of Comparative Medicine and Departments of,
Zhong-Wu Liu: Obstetrics, Gynecology & Reproductive Sciences
Nicholas Walllingford: Obstetrics, Gynecology & Reproductive Sciences
Derek M. Erion: Obstetrics, Gynecology & Reproductive Sciences
Erzsebet Borok: Obstetrics, Gynecology & Reproductive Sciences
Jeffery M. Friedman: Laboratory of Molecular Genetics, Howard Hughes Medical Institute, Rockefeller University, New York, New York 10021, USA
Matthias H. Tschöp: University of Cincinnati, Cincinnati, Ohio 45237, USA
Marya Shanabrough: Obstetrics, Gynecology & Reproductive Sciences
Gary Cline: Internal Medicine, Howard Hughes Medical Institute and,
Gerald I. Shulman: Internal Medicine, Howard Hughes Medical Institute and,
Anna Coppola: Obstetrics, Gynecology & Reproductive Sciences
Xiao-Bing Gao: Obstetrics, Gynecology & Reproductive Sciences
Tamas L. Horvath: Section of Comparative Medicine and Departments of,
Sabrina Diano: Obstetrics, Gynecology & Reproductive Sciences

Nature, 2008, vol. 454, issue 7206, 846-851

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07181

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