UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals.
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.
Andrews
Zane B
ZB
Section of Comparative Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Howard Hughes Medical Institute, New York, New York 10021, USA.
Liu
Zhong-Wu
ZW
Walllingford
Nicholas
N
Erion
Derek M
DM
Borok
Erzsebet
E
Friedman
Jeffery M
JM
Tschöp
Matthias H
MH
Shanabrough
Marya
M
Cline
Gary
G
Shulman
Gerald I
GI
Coppola
Anna
A
Gao
Xiao-Bing
XB
Horvath
Tamas L
TL
Diano
Sabrina
S
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
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