OR12-3 Mice with MC4R Site Mutation (F51L) Develop Severe Obesity Independent of Gs-alpha/cAMP Signaling

• DOI: 10.1210/js.2019-or12-3
• Publication Date: 2019-05-10T02:12:02Z
• Authors: Peter Metzger; Bradley Carlson; Hui Sun; Zhenzhong Cui; Oksana Gavrilova; Min Chen; Lee Weinstein
• Keywords: Melanocortin 4 receptor; Energy homeostasis

The central melanocortin α-MSH acts through MC4R receptors, which are known to activate Gsα/cAMP signaling, promote negative energy balance by inhibiting food intake (FI) and stimulating expenditure (EE). However, we have shown that mice with Gsα deficiency become obese decreased EE but without hyperphagia, inhibition of in the paraventricular nucleus hypothalamus (PVN) is mediated via G proteins Gqα/G11α. Previous vitro studies also several mutations associated early-onset human obesity, including F51L, no effect on signaling. To determine whether there Gsα/cAMP-independent signaling pathways regulate homeostasis MC4Rs vivo, generated an site mutation at F51L (MC4RF51L) using CRISPR/Cas9 studied its metabolic consequences. MC4RF51L developed severe obesity increased fat mass body length, primarily FI. In response i.p. administered MC3R/MC4R agonist MTII, showed impaired FI stimulation. When MTII was directly administrated a cannula unilaterally implanted into PVN, markedly inhibited WT mice, not while heart rate stimulated both mice. contrast, PVN administration did affect either or CREB phosphorylation levels were similarly elevated following injection confirming pathway intact these mutants. addition, had reduced glucose tolerance insulin sensitivity secondary as intolerance seen non-obese young normal temperature room (22oC) maintained their when exposed 6oC for 5 hours, consistent thermogenic acute cold conditions. Taken together, our data show MC4R/Gsα/cAMP required MTII-inhibited activation has observable EE. Thus, results additional provide support mediate actions protein other than Gsα, most likely This work supported Intramural Research Program National Institute Diabetes Digestive Kidney Diseases.