Hypothalamic C2‐domain protein (C2CD5) involved in protein trafficking and food intake

Abstract

Rates of overweight and obesity epidemic have risen significantly in the past few decades, and 34% of adults and 15–20% of children and adolescents in the United States are now obese. Melanocortin receptor 4 (MC4R), contributes to appetite control in hypothalamic neurons and is a promising target for anti‐obesity treatments or drug development. While the presence of functional MC4R is crucial for normal neural control of homeostasis and is altered in obesity and in presence of lipids, the mechanisms underlying altered MC4R trafficking are unknown.Our studies identified a novel C2‐domain protein, C2CD5 that appears to contribute to the regulation of MC4R trafficking. We found that 1) the expression of C2CD5 is decreased in diet‐induced obesity models compared to controls, 2) C2CD5 knock‐out mice exhibit pronounced obesity partially due to an increase in food intake compared to control mice when fed a high‐fat diet, 3) C2CD5 colocalize and interacts with MC4R complex, 4) loss of functional C2CD5 alters MC4R endocytosis, and, 5) C2CD5 knock‐out mice exhibit decreased acute responses to Melanotan‐II injection into the paraventricular hypothalamus.Based on these, we hypothesize that hypothalamic C2CD5 is a MC4R trafficking protein that responds to metabolic cues and is involved in neural control of energy balance. These studies provide evidence for a novel pathway and targets, to develop therapeutic drugs potentially to rescue energy balance defects that contribute to the development and maintenance of obesity.Support or Funding InformationThis study was supported by AHA SDG and Loyola University Chicago to VMA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.