Liver-Specific Reactivation of MC3R Partially Reverses the Obesity of MC3R Deficiency

Abstract

The Melanocortin 3 Receptor (MC3R) regulates appetite, food intake, and energy expenditure in humans and mice. MC3R is primarily expressed in the hypothalamus and other CNS regions but is also present in peripheral tissues including the liver. Total body knockouts of MC3R have a distinct obese phenotype of increased fat mass with decreased lean mass. However, when MC3R is reactivated only in the brain of mice that are globally MC3R deficient, the obese phenotype is not completely recovered compared to wild type mice, suggesting peripheral MC3R may also regulate energy homeostasis. To begin to examine the role of peripheral MC3R in energy balance, we investigated the extent to which liver specific reactivation of MC3R reversed the obese phenotype seen in the global knockout. We generated a liver specific MC3R recovery model by crossing a floxed-transcription blocker MC3R (MC3R-/-) mouse line with mice expressing albumin-Cre recombinase (Alb-Cre+/+); both strains were in a C57BL/6J (BL/6) background. We measured the body weight and body composition (using dual energy X-ray absorptiometry) of 10-12-week-old MC3R-/-, MC3R-/- + Alb-Cre +/-, and MC3R-/- + Alb-Cre +/+ and BL/6 mice. We found amongst female mice that expression of Alb-Cre (reactivating only hepatic MC3R) was sufficient to partially reverse the increased percentage fat mass of MC3R-/- (MC3R-/-: n=15, 22.15 ± 4.78%; MC3R-/- + Alb-Cre +/- : n=5, 21.22 ± 3.13%; MC3R-/- + Alb-Cre +/+ : n=3, 17.83 ± 4.04%; BL/6: n=17, 15.72 ± 3.18%; p < 0.0001). A similar pattern of partial recovery was also observed for fat grams (p=0.0009), % lean mass (p=0.0003), and lean grams (p=0.002), with no differences in body weight amongst genotypes (p=0.612). Data for male mice were insufficient to perform analyses at this time. We conclude hepatic MC3R is an important regulator of energy homeostasis and body composition. The potential roles for MC3R in other tissues where it is expressed remain to be determined. Disclosure N.J. Levi: None. J. Jun: None. T.P. Patel: None. A.J. Uhlman: None. R. Roberson: None. J.A. Yanovski: Research Support; Self; Rhythm Pharmaceuticals Inc., Zafgen.