LATS2 kinase integrates Hippo signalling with PPARγ repression to control brown adipocyte thermogenesis and systemic energy balance

Brown and beige adipocytes promote metabolic health through adaptive thermogenesis, yet the molecular mechanisms that govern their function remain incompletely understood. Here, we identify the Large Tumor Suppressor kinases (LATS), central regulators of the Hippo pathway, as key modulators of brown adipocyte activity and systemic energy homeostasis. We demonstrate that LATS kinases, particularly LATS2, modulate thermogenic gene expression, UCP1 protein levels and mitochondrial respiration by controlling the stability and nuclear localization of the transcriptional co-regulator TAZ. Mechanistically, silencing of LATS kinases leads to TAZ stabilization, which represses the activity of the master regulator PPARγ, impairing thermogenic activation. In vivo, brown adipocyte-specific deletion of Lats1 and Lats2 in mice reduces UCP1 protein levels and thermogenic potential during cold exposure without altering brown adipocyte identity. Remarkably, Lats1 and Lats2 deletion in brown fat suppresses food intake and protects against diet-induced obesity independently of ambient temperature or UCP1 function. Transcriptomic analysis of brown adipose tissue identifies Vnn1, Mfge8, S100b, and Angptl3, as potential BAT-derived regulators of appetite. These findings uncover the LATS–TAZ–PPARγ axis as a critical regulator of brown adipocyte thermogenesis and identify a previously unrecognized role of LATS kinases in controlling systemic energy homeostasis via non-thermogenic BAT functions.