Melanocortin 3 receptor (MC3R), a regulator of hepatic autophagy in obesity

Authors

• JY Jun
• A Seo
• P Patel
• A Uhlman
• T Patel
• S Cai
• F Famuyiwa
• H Bednar
• N Levi
• R Roberson
• A Demidowich
• J Yanovski

Abstract

Autophagy plays a pivotal role in cell metabolism and quality control. Defective cellular autophagy has been reported in human diseases, including obesity. We previously have reported that humans with MC3R hypoactive mutations (C17A + G241A) had increased BMI, producing more adipose tissue expansion than humans without mutations. However, the precise mechanisms that MC3R modulates to alter metabolic homeostasis remain unclear. Based on the evidence of the essential role of hepatic autophagy in metabolism, we hypothesized that the peripheral MC3R signaling modulates autophagic degradation in obesity. To investigate the role of MC3R in autophagy regulation, we generated humanized knock-in mouse models that carry either wild-type (MC3RhWT/hWT) or hypoactive human double mutant (MC3RhDM/hDM) MC3R. MC3RhDM/hDM mice exhibit an obese phenotype with significantly greater fat mass and hepatic triglycerides, which are similar in phenotype to MC3R-/- compared to MC3RhWT/hWT or C57/BL6 mice. First, we demonstrated that primary hepatocytes treated with the MC3R specific agonist D-trp-gamma-MSH had significantly induced LC3II, the marker of autophagosome formation, suggesting the possible role of MC3R in autophagy. Second, we found overnight fasting induced hepatic LC3 II in MC3RhWT/hWT and C57/BL6, but not in MC3RhDM/hDM or MC3R-/-; rather there was significant upregulation of basal LC3 II in the fed state. Next, although primary cultured hepatocytes from MC3RhWT/hWT had substantial induction of autophagic flux after chloroquine treatment with or without starvation, cells from MC3RhDM/hDM and MC3R-/- failed to show autophagic flux, suggesting MC3R may play a role in the regulation of autolysosomal degradation in hepatic autophagy. In conclusion, hypoactive MC3R mutation or the absence of peripheral MC3R appears to cause dysregulation of hepatic autophagy, thus contributing to the accumulation of hepatic lipid content. Altered autophagy may be part of the explanation for the increased prevalence of childhood obesity among humans with hypoactive MC3R.

Scientific Focus Area: Cell Biology

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