1. Section of Comparative Medicine and Departments of,
2. Obstetrics, Gynecology & Reproductive Sciences
3. Internal Medicine, Howard Hughes Medical Institute and,
4. Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
5. Department of Neurobiology, Yunyang Medical College, Shiyan, Hubei 442000, China
6. Laboratory of Molecular Genetics, Howard Hughes Medical Institute, Rockefeller University, New York, New York 10021, USA
7. Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45237, USA

Correspondence to: Tamas L. Horvath^1,2,4Sabrina Diano^2,4 Correspondence and requests for materials should be addressed to T.L.H. (Email: tamas.horvath@yale.edu) or S.D. (Email: sabrina.diano@yale.edu).

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.

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