Sphingosine kinase 2 regulates adipocyte browning and whole-body metabolism [CUT&Tag]

Obesity increases circulating levels of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). Here, we identify adipocyte-expressed sphingosine kinase 2 (SPHK2), an enzyme that produces S1P, as a regulator of adipose tissue browning. Mice with adipocyte-specific deletion of Sphk2 were protected from Western diet-induced obesity concomitantly with elevated energy expenditure and browning of subcutaneous fat and enhanced expression of Ucp1 and key thermogenic genes, resulting in reduced adiposity and hepatic steatosis, improved glucose tolerance and insulin sensitivity. Mechanistically, obesogenic diet promoted nuclear localization of SPHK2 in adipocytes, where it cooperated with transcription factors to suppress the thermogenic transcriptome. Adipocyte SPHK2 was responsible for maintaining homeostatic circulating S1P levels and driving the pathogenic rise of S1P in response to obesogenic diet. Our findings reveal a distinct role of adipocyte SPHK2 in regulation of the thermogenic program important for whole-body metabolic homeostasis and energy expenditure and highlights SPHK2 as a potential therapeutic target for treatment of metabolic disorders.