OR30-3 The G Proteins Gqα/G11α and Gsα Mediate Distinct Physiological Responses to Central Melanocortins

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR30-Central Regulation of Appetite & Feeding
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:45 AM
Room 304 (Moscone Center)
Yong-Qi Li*1, Min Chen1, Mritunjay Pandey1, Ahmed Kablan1, Yogendra Shrestha1, Oksana Gavrilova2, Stefan Offermanns3 and Lee Scott Weinstein1
1NIH/NIDDK, Bethesda, MD, 2NIH/NIDDK, 3Max-Planck-Institute for Heart and Lung Research, Bad Neuheim, Germany
Mutations of the G protein-coupled melanocortin-4 receptor (MC4R) are the most common cause of monogenic obesity. MC4R deficiency in both humans and mice leads to several physiological defects, including increased food intake, fat mass and body length and reduced sympathetic nerve activity (SNA), energy expenditure, and insulin sensitivity. Pseudohypoparathyroidism type 1A (PHP1A) is another monogenic obesity disorder resulting from heterozygous inactivating mutations on the gene for Gsα, the ubiquitous G protein that couples receptors, including MC4R, to intracellular cAMP production. We previously showed that mice with brain-specific disruption of the Gsα maternal allele (mBrGsKO) develop obesity associated with reduced SNA and energy expenditure, as well as peripheral insulin resistance prior to the onset of obesity, but do not show a primary defect in food intake or body length. The ability of mBrGsKO mice to increase their energy expenditure in response to the MC4R agonist MTII is impaired, while MTII inhibition of food intake is unaffected. It therefore appears that MC4R mediates its effects on body length and food intake via Gsα-independent pathways. We hypothesized that these Gsα-independent MC4R effects may be mediated by another G protein family Gq/11α that primarily couples receptors to activation of phospholipase C. As MC4R controls food intake primarily in the paraventricular nucleus of hypothalamus (PVN), we generated a mouse line with PVN-specific loss of Gq/11α (PVNGq/11KO: Sim1-cre+, Gqαflox/flox, G11α-/-). Like MC4R knockout mice and in contrast to mBrGsKO mice, PVNGq/11KO mice had marked obesity due to hyperphagia and increased body length without primary effects on energy expenditure or insulin sensitivity. In contrast to mBrGsKO mice, MTII inhibition of food intake was impaired while MTII stimulation of energy expenditure was unaffected. Sim1 and CRH expression in PVN was significantly reduced, and serum ACTH and corticosterone levels were markedly reduced. Our results show that physiological effects of central melanocortins are mediated by distinct G protein pathways: food intake and body length via Gq/11α in PVN; SNA, energy expenditure and insulin sensitivity via Gsα in areas outside the PVN. Gq/11α signaling in PVN is also critical in regulation of the HPA axis. Biased MC4R agonists that specifically activate Gq/11α but not Gsα may be potential agents to suppress appetite without untoward SNS-mediated cardiovascular side effects.

Nothing to Disclose: YQL, MC, MP, AK, YS, OG, SO, LSW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was funded by the Intramural Research Program of NIDDK, NIH.