title: UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals.
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.
authors.affiliation: Section of Comparative Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Howard Hughes Medical Institute, New York, New York 10021, USA.
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
authors.forename: Zhong-Wu
authors.initials: ZW
authors.lastname: Liu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Walllingford
authors.forename: Derek M
authors.initials: DM
authors.lastname: Erion
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Borok
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Friedman
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Marya
authors.initials: M
authors.lastname: Shanabrough
authors.forename: Gary
authors.initials: G
authors.lastname: Cline
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Anna
authors.initials: A
authors.lastname: Coppola
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Gao
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Sabrina
authors.initials: S
authors.lastname: Diano
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D054439:Ghrelin / Q000378:metabolism* / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D054369:Agouti-Related Protein; D005227:Fatty Acids; D054439:Ghrelin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D002334:Carnitine O-Palmitoyltransferase