Cell Metab. 2025 Oct 23:S1550-4131(25)00433-4. doi: 10.1016/j.cmet.2025.09.014
Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism
Jérémy Dufau1, Emeline Recazens1, Laura Bottin1, Camille Bergoglio1, Aline Mairal1, Karima Chaoui2, Marie-Adeline Marques1, Veronica Jimenez3, Miquel García3, Tongtong Wang4, Henrik Laurell1, Jason S Iacovoni1, Remy Flores-Flores1, Pierre-Damien Denechaud1, Khalil Acheikh Ibn Oumar1, Ez-Zoubir Amri5, Catherine Postic6, Jean-Paul Concordet7, Pierre Gourdy8, Niklas Mejhert9, Mikael Rydén9, Odile Burlet-Schiltz2, Fatima Bosch3, Christian Wolfrum4, Etienne Mouisel1, Genevieve Tavernier10, Dominique Langin11
Affiliations
1I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Inserm, Toulouse, France.
2IPBS, Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Toulouse, France.
3Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBERDEM, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
4Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
5iBV, Université Côte d’Azur, CNRS, Inserm, Adipo-Cible Research Study Group, Nice, France.
6Institut Cochin, Université de Paris, CNRS, Inserm, Paris, France.
7Museum National d’Histoire Naturelle, Inserm, CNRS, Laboratoire Structure et Instabilité des Génomes, Paris, France.
8I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Inserm, Toulouse, France; Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
9Department of Medicine (H7), Karolinska Institutet, and Karolinska University Hospital, ME Endokrinologi, Stockholm, Sweden.
10I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Inserm, Toulouse, France; CREFRE-ANEXPLO, Université de Toulouse, Inserm, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France.
11I2MC, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Inserm, Toulouse, France; Centre Hospitalier Universitaire de Toulouse, Toulouse, France; IUF, Institut Universitaire de France, Paris, France.
Abstract
In adipocytes, hormone-sensitive lipase (HSL) plays a key role in hydrolyzing triacylglycerols that are stored in lipid droplets. Contrary to the expected phenotype, HSL-deficient mice and humans exhibit lipodystrophy. Here, we show that HSL is also present in the adipocyte nucleus. Mouse models with different HSL subcellular localizations reveal that nuclear HSL is essential for the maintenance of adipose tissue. Gene silencing in human adipocytes shows that HSL, independently of its enzymatic activity, exerts opposing effects on mitochondrial oxidative phosphorylation and the extracellular matrix. Mechanistically, we found that HSL accumulates in the nucleus by interacting with the transforming growth factor β (TGF-β) signaling mediator, mothers against decapentaplegic homolog 3 (SMAD3). Conversely, HSL phosphorylation induces nuclear export. In vivo, HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting. Together, our data show that as both a cytosolic enzyme and a nuclear factor, HSL plays a pivotal role in adipocyte biology and adipose tissue maintenance.