Melanocortin 3 receptor regulates hepatic autophagy and systemic adiposity
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.
Authors
- Noah J. Levi (ORCID: https://orcid.org/0000-0002-2854-9113)
- Mark D. Ericson (ORCID: https://orcid.org/0000-0002-8715-6010)
- Nicol Tugarinov (ORCID: https://orcid.org/0000-0003-0918-9172)
- Jocelyn Chen
- Adrian M. Wong (ORCID: https://orcid.org/0000-0003-3919-0705)
- Anna T Wolska (ORCID: https://orcid.org/0000-0001-9479-0741)
- Joo Yun Jun
- Antony Cougnoux (ORCID: https://orcid.org/0000-0001-9407-7540)
- Pooja Patel (ORCID: https://orcid.org/0000-0002-5345-0158)
- Tushar Patel (ORCID: https://orcid.org/0000-0002-7823-2579)
- Diana M. Elizondo
- Jack Adam Yanovski (ORCID: https://orcid.org/0000-0001-8542-1637)
- Daniel B. Gehle (ORCID: https://orcid.org/0000-0003-4629-7615)
- Elizabeth K. Altman (ORCID: https://orcid.org/0000-0002-4185-5203)
- Tamar Demby (ORCID: https://orcid.org/0000-0002-8300-4239)
- Carrie Haskell‐Luevano (ORCID: https://orcid.org/0000-0002-6783-5972)
- Arnold Y. Seo (ORCID: https://orcid.org/0000-0002-4607-8925)
- Sun Min Jung
Institutions
- University of Minnesota (US)
- Howard Hughes Medical Institute (US)
- Janelia Research Campus (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- National Heart, Lung, and Blood Institute (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-16
- DOI
- https://doi.org/10.1038/s41467-025-56936-1
- Citations
- 7
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 9.48
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- RIKEN
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development