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. • Hormone-sensitive lipase is localized within the nuclei of adipocytes • In vivo , nuclear HSL levels regulate adipose tissue mass • In vitro , nuclear HSL controls mitochondria and extracellular matrix gene expression • HSL nuclear level is regulated by TGF-β and PKA signaling pathways Dufau, Recazens, et al. identified the neutral lipase HSL in the nucleus of adipocytes, where it modulates gene expression. The trafficking of HSL between the nucleus and the cytosol is under the control of TGF-β and catecholamine signaling. In vivo , the presence of nuclear HSL is crucial for adipose tissue development.