Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism
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.
Authors
- Geneviève Tavernier (ORCID: https://orcid.org/0000-0002-0214-0344)
- Jean‐Paul Concordet (ORCID: https://orcid.org/0000-0001-8924-4316)
- Étienne Mouisel (ORCID: https://orcid.org/0000-0002-4676-5709)
- Christian Wolfrum (ORCID: https://orcid.org/0000-0002-3862-6805)
- Fátima Bosch (ORCID: https://orcid.org/0000-0002-7705-5515)
- Verónica A. Jiménez (ORCID: https://orcid.org/0000-0002-6783-5657)
- Dominique Langin (ORCID: https://orcid.org/0000-0002-2669-7825)
- Mikael Rydén (ORCID: https://orcid.org/0000-0003-4785-1876)
- Aline Mairal
- Henrik Laurell (ORCID: https://orcid.org/0000-0001-7328-935X)
- Rémy Florès-Florès (ORCID: https://orcid.org/0009-0007-4053-4954)
- Pierre Gourdy (ORCID: https://orcid.org/0000-0002-5362-3813)
- Camille Bergoglio (ORCID: https://orcid.org/0000-0003-1394-7677)
- Catherine Postic (ORCID: https://orcid.org/0000-0002-1875-6960)
- Emeline Recazens (ORCID: https://orcid.org/0000-0003-3800-7411)
- Miquel García (ORCID: https://orcid.org/0000-0002-1602-4993)
- Pierre‐Damien Denechaud (ORCID: https://orcid.org/0000-0003-3502-4814)
- Jason S. Iacovoni
- Odile Burlet‐Schiltz (ORCID: https://orcid.org/0000-0002-3606-2356)
- Ez‐Zoubir Amri
- Laure Bottin
- Niklas Mejhert
- Karima Chaoui (ORCID: https://orcid.org/0009-0001-4861-0102)
- Jérémy Dufau (ORCID: https://orcid.org/0000-0002-1900-2298)
- Tongtong Wang (ORCID: https://orcid.org/0000-0002-8807-2441)
- Marie-Adeline Marqués
- Khalil Acheikh Ibn Oumar
Institutions
- Universitat Autònoma de Barcelona (ES)
- Centre National de la Recherche Scientifique (FR)
- Karolinska University Hospital (SE)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Institut Universitaire de France (FR)
- Université Côte d'Azur (FR)
- Board of the Swiss Federal Institutes of Technology (CH)
- Karolinska Institutet (SE)
- Centre Hospitalier Universitaire de Toulouse (FR)
- ETH Zurich (CH)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Institut de Pharmacologie et de Biologie Structurale (FR)
- Institut de Biologie Valrose (FR)
- Institut Cochin (FR)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
- Structure et Instabilité des Génomes (FR)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1016/j.cmet.2025.09.014
- Citations
- 2
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- AstraZeneca
- Univerzita Karlova v Praze
- European Commission
- European Foundation for the Study of Diabetes
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Novo Nordisk
- Centre National de la Recherche Scientifique
- AstraZeneca France
- Région Occitanie Pyrénées-Méditerranée
- Agencia Estatal de Investigación