Nuclear hormone-sensitive lipase controls adipocyte function

Hormone-sensitive lipase (HSL) is a neutral lipase which hydrolyses fat stored as triacylglycerols in adipocyte lipid droplets. Its activity is under the control of hormones and neurotransmitters through protein kinase (PK)-mediated phosphorylation. Here we show that HSL is expressed in the nucleus where it controls the biological functions of the adipocyte. Gene editing reveals that the development of adipose tissue in vivo relies on nuclear HSL. In the nucleus, HSL interacts with a network of proteins involved in transcriptional and post-transcriptional events. TGFβ activation of SMAD3 promotes HSL nuclear accumulation whereas PKA-mediated phosphorylation induces HSL nuclear export. HSL nuclear content is increased in obese mouse adipose tissue whereas expression of a catalytically inactive nuclear HSL impairs glucose homeostasis. These findings reveal that nuclear HSL is essential for the maintenance of adipocyte function. HSL integrates signals from the TGFβ and catecholamine signaling pathways and controls adipocyte mitochondrial oxidative activity.