Hepatic MC3R is a regulator of lipid droplet autophagy and liver steatosis

Intrahepatic triglyceride breakdown and recycling occur through lipolysis and lipid droplet (LD) macroautophagy/autophagy to regulate systemic fat partitioning. We recently demonstrated that MC3R is important for hepatic autophagy and peripheral metabolism, beyond its established functions in the CNS, where it affects energy homeostasis, feeding regulation, and puberty. MC3R agonists activate hepatocyte autophagy through LC3-II activation, TFEB cytoplasmic-to-nuclear translocation, and subsequent downstream autophagy gene activation. Global <i>mc3r</i> knockout mice develop obesity with increased hepatic triglyceride accumulation and blunted hepatocellular autophagosome-lysosome docking, leading to defective lipid droplet clearance. Hepatic <i>Mc3r</i> reactivation in global knockouts improves hepatocellular autophagy, lipid metabolism, mitochondrial respiration, energy expenditure, body fat, and body weight. These results reveal an autonomous role for hepatic MC3R in regulating lipid droplet autophagy, liver steatosis, and systemic adiposity.<b>Abbreviation</b>: AP:autophagosome; CNS:central nervous system; EIF4EBP1: eukaryotic translation initiationfactor 4E binding protein 1; EM: electron microscopy; LD: lipiddroplets; GFP: green fluorescent protein; MAFLD: metabolic-associatedfatty liver disease; MAP1LC3/LC3-II: microtubule-associated protein 1light chain 3-II; MC3R: melanocortin 3 receptor; MTORC1: mechanistictarget of rapamycin kinase complex 1; NDP-42:norleucine D-phenylalanine compound-42; TFEB: transcriptionfactor EB.