Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism

Jérémy Dufau; Emeline Recazens; Laura Bottin; Camille Bergoglio; Aline Mairal; Karima Chaoui; Marie-Adeline Marques; Veronica Jimenez; Miquel García; Tongtong Wang; Henrik Laurell; Jason S. Iacovoni; Remy Flores-Flores; Pierre-Damien Denechaud; Khalil Acheikh Ibn Oumar; Ez-Zoubir Amri; Catherine Postic; Jean-Paul Concordet; Pierre Gourdy; Niklas Mejhert; Mikael Rydén; Odile Burlet-Schiltz; Fatima Bosch; Christian Wolfrum; Etienne Mouisel; Genevieve Tavernier; Dominique Langin

doi:10.1016/j.cmet.2025.09.014

Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism

Jérémy Dufau, Emeline Recazens, Laura Bottin, Camille Bergoglio, Aline Mairal, Karima Chaoui, Marie-Adeline Marques, Veronica Jimenez, Miquel García, Tongtong Wang, Henrik Laurell, Jason S. Iacovoni, Remy Flores-Flores, Pierre-Damien Denechaud, Khalil Acheikh Ibn Oumar, Ez-Zoubir Amri, Catherine Postic, Jean-Paul Concordet, Pierre Gourdy, Niklas MejhertMikael Rydén, Odile Burlet-Schiltz, Fatima Bosch, Christian Wolfrum, Etienne Mouisel, Genevieve Tavernier, Dominique Langin

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Resum

En els adipòcits, la lipasa sensible a hormones (HSL) té un paper clau en la hidròlisi dels triacilglicerols que s'emmagatzemen en gotes de lípids. Contràriament al fenotip esperat, els ratolins i humans amb deficiència d'HSL mostren lipodistròfia. Aquí mostrem que l'HSL també és present en el nucli adipòcits. Els models de ratolí amb diferents localitzacions subcel·lulars d'HSL revelen que l'HSL nuclear és essencial per al manteniment del teixit adipós. El silenciament gènic en els adipòcits humans mostra que HSL, independentment de la seva activitat enzimàtica, exerceix efectes oposats sobre la fosforilació oxidativa mitocondrial i la matriu extracel·lular. Mecànicament, hem trobat que l'HSL s'acumula al nucli interactuant amb el mediador del senyal del factor de creixement transformador β (TGF-β), les mares contra decapentaplegic homòleg 3 (SMAD3). Al contrari, la fosforilació d'HSL indueix exportació nuclear. In vivo, l'HSL s'acumula al nucli dels adipòcits durant una alimentació amb alt contingut de greixos amb l'efecte invers durant el dejuni. Junts, les nostres dades mostren que tant com un enzim citosòlic i un factor nuclear, HSL té un paper fonamental en la biologia d'adipòcit i manteniment del teixit adipós.

Idioma original	Anglès
Pàgines (de-a)	2250-2263.e9
Nombre de pàgines	24
Revista	Cell Metabolism
Volum	37
Número	11
DOIs	https://doi.org/10.1016/j.cmet.2025.09.014
Estat de la publicació	Publicada - 4 de nov. 2025

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Dufau, J., Recazens, E., Bottin, L., Bergoglio, C., Mairal, A., Chaoui, K., Marques, M.-A., Jimenez, V., García, M., Wang, T., Laurell, H., Iacovoni, J. S., Flores-Flores, R., Denechaud, P.-D., Oumar, K. A. I., Amri, E.-Z., Postic, C., Concordet, J.-P., Gourdy, P., ... Langin, D. (2025). Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism. Cell Metabolism, 37(11), 2250-2263.e9. https://doi.org/10.1016/j.cmet.2025.09.014

@article{68c6efa6eb9e4c1d802e458505a40d33,

title = "Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism",

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.",

keywords = "hormone-sensitive lipase, adipocyte, adipose tissue, cell nucleus, protein-protein interaction, TGF-β signaling, mitochondrial oxidative phosphorylation, extracellular matrix, obesity, lipodystrophy",

author = "J{\'e}r{\'e}my Dufau and Emeline Recazens and Laura Bottin and Camille Bergoglio and Aline Mairal and Karima Chaoui and Marie-Adeline Marques and Veronica Jimenez and Miquel Garc{\'i}a and Tongtong Wang and Henrik Laurell and Iacovoni, \{Jason S.\} and Remy Flores-Flores and Pierre-Damien Denechaud and Oumar, \{Khalil Acheikh Ibn\} and Ez-Zoubir Amri and Catherine Postic and Jean-Paul Concordet and Pierre Gourdy and Niklas Mejhert and Mikael Ryd{\'e}n and Odile Burlet-Schiltz and Fatima Bosch and Christian Wolfrum and Etienne Mouisel and Genevieve Tavernier and Dominique Langin",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

year = "2025",

month = nov,

day = "4",

doi = "10.1016/j.cmet.2025.09.014",

language = "English",

volume = "37",

pages = "2250--2263.e9",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "11",

}

Dufau, J, Recazens, E, Bottin, L, Bergoglio, C, Mairal, A, Chaoui, K, Marques, M-A, Jimenez, V, García, M, Wang, T, Laurell, H, Iacovoni, JS, Flores-Flores, R, Denechaud, P-D, Oumar, KAI, Amri, E-Z, Postic, C, Concordet, J-P, Gourdy, P, Mejhert, N, Rydén, M, Burlet-Schiltz, O, Bosch, F, Wolfrum, C, Mouisel, E, Tavernier, G & Langin, D 2025, 'Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism', Cell Metabolism, vol. 37, núm. 11, pàg. 2250-2263.e9. https://doi.org/10.1016/j.cmet.2025.09.014

TY - JOUR

T1 - Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism

AU - Dufau, Jérémy

AU - Recazens, Emeline

AU - Bottin, Laura

AU - Bergoglio, Camille

AU - Mairal, Aline

AU - Chaoui, Karima

AU - Marques, Marie-Adeline

AU - Jimenez, Veronica

AU - García, Miquel

AU - Wang, Tongtong

AU - Laurell, Henrik

AU - Iacovoni, Jason S.

AU - Flores-Flores, Remy

AU - Denechaud, Pierre-Damien

AU - Oumar, Khalil Acheikh Ibn

AU - Amri, Ez-Zoubir

AU - Postic, Catherine

AU - Concordet, Jean-Paul

AU - Gourdy, Pierre

AU - Mejhert, Niklas

AU - Rydén, Mikael

AU - Burlet-Schiltz, Odile

AU - Bosch, Fatima

AU - Wolfrum, Christian

AU - Mouisel, Etienne

AU - Tavernier, Genevieve

AU - Langin, Dominique

PY - 2025/11/4

Y1 - 2025/11/4

N2 - 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.

AB - 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.

KW - hormone-sensitive lipase

KW - adipocyte

KW - adipose tissue

KW - cell nucleus

KW - protein-protein interaction

KW - TGF-β signaling

KW - mitochondrial oxidative phosphorylation

KW - extracellular matrix

KW - obesity

KW - lipodystrophy

UR - https://www.scopus.com/pages/publications/105020161898

UR - https://www.mendeley.com/catalogue/e837af27-ccf3-3131-b74c-c1ddeabc7ee9/

U2 - 10.1016/j.cmet.2025.09.014

DO - 10.1016/j.cmet.2025.09.014

M3 - Article

C2 - 41135514

SN - 1550-4131

VL - 37

SP - 2250-2263.e9

JO - Cell Metabolism

JF - Cell Metabolism

IS - 11

ER -

Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism

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