Melanocortin 3 receptor regulates hepatic autophagy and systemic adiposity

Tushar P. Patel, Joo Yun Jun, Arnold Y. Seo, Noah J. Levi, Diana M. Elizondo, Jocelyn Chen, Adrian M. Wong, Nicol Tugarinov, Elizabeth K. Altman, Daniel B. Gehle, Sun Min Jung, Pooja Patel, Mark Ericson, Carrie Haskell-Luevano, Tamar C. Demby, Antony Cougnoux, Anna Wolska and Jack A. Yanovski ()
Additional contact information
Tushar P. Patel: NIH
Joo Yun Jun: NIH
Arnold Y. Seo: Howard Hughes Medical Institute (HHMI)
Noah J. Levi: NIH
Diana M. Elizondo: NIH
Jocelyn Chen: NIH
Adrian M. Wong: NIH
Nicol Tugarinov: NIH
Elizabeth K. Altman: NIH
Daniel B. Gehle: NIH
Sun Min Jung: NIH
Pooja Patel: NIH
Mark Ericson: University of Minnesota College of Pharmacy
Carrie Haskell-Luevano: University of Minnesota College of Pharmacy
Tamar C. Demby: NIH
Antony Cougnoux: NIH
Anna Wolska: NIH
Jack A. Yanovski: NIH

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Systemic lipid homeostasis requires hepatic autophagy, a major cellular program for intracellular fat recycling. Here, we find melanocortin 3 receptor (MC3R) regulates hepatic autophagy in addition to its previously established CNS role in systemic energy partitioning and puberty. Mice with Mc3r deficiency develop obesity with hepatic triglyceride accumulation and disrupted hepatocellular autophagosome turnover. Mice with partially inactive human MC3R due to obesogenic variants demonstrate similar hepatic autophagic dysfunction. In vitro and in vivo activation of hepatic MC3R upregulates autophagy through LC3II activation, TFEB cytoplasmic-to-nuclear translocation, and subsequent downstream gene activation. MC3R-deficient hepatocytes had blunted autophagosome-lysosome docking and lipid droplet clearance. Finally, the liver-specific rescue of Mc3r was sufficient to restore hepatocellular autophagy, improve hepatocyte mitochondrial function and systemic energy expenditures, reduce adipose tissue lipid accumulation, and partially restore body weight in both male and female mice. We thus report a role for MC3R in regulating hepatic autophagy and systemic adiposity.

Date: 2025
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DOI: 10.1038/s41467-025-56936-1

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