The hormone ghrelin is produced in the gut and acts through heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors on neurons in the brain to stimulate food intake. Andrews et al. analyzed the effects of ghrelin on so-called NPY/AgRP neurons (named for their expression of two proteins—neuropeptide Y and agouti-related protein) of the hippocampus. In other tissues, including liver and adipose tissue, ghrelin influences metabolism by enhancing expression of uncoupling protein 2. Uncoupling protein 2 is a member of the anion carrier protein superfamily that exists in the inner membrane of mitochondria. Uncoupling refers to leaking of protons across the mitochondrial membrane that thus uncouples the electrochemical gradient across the membrane from formation of ATP (adenosine triphosphate) by altering the flow of electrons through the respiratory chain, a process that generates superoxide radicals in the mitochondria. The authors found that ghrelin also increased accumulation of UCP2 in the NPY/AgRP neurons, and studies with preparations from Ucp2–/– mice showed that enhanced respiration in the neurons and neuronal firing in response to ghrelin required UCP2. The Ucp2–/– animals also showed diminished feeding response to ghrelin. The authors further traced ghrelin’s actions through activation of adenosine monophosphate (AMP)–activated protein kinase and consequent increased activity of carnitine palmitoyltransferase, which enhances oxidation of long-chain fatty acids. Sustained metabolism of long-chain fatty acids increases production of reactive oxygen species (ROS), and ghrelin appeared to act through UCP2 to diminish accumulation of ROS. Limiting ROS allows continued fueling of firing of NPY/AgRP neurons and enhances their output, which, in turn, leads to increased feeding.
Z. B. Andrews, Z.-W. Liu, N. Wallingford, D. M. Erion, E. Borok, J. M. Friedman, M. H. Tschöp, M. Shanabrough, G. Cline, G. I. Shulman, A. Coppola, X.-B. Gao, T. L. Horvath, S. Diano, UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846-851 (2008). [PubMed]