Delineation of cold-responsive stimulation of lipolysis by hormone-sensitive lipase to increase thermogenesis in brown fat

Cold stimulates adrenergic signaling to trigger rapid lipolysis in brown adipose tissue (BAT) for adaptive thermogenesis. Protein kinase A (PKA) and hormone-sensitive lipase (HSL) are required in mediating the adrenergic signaling; however, the mechanism underlying HSL activation and translocation to lipid droplets remains unclear. Here, we demonstrate that cold-induced activation of PKA phosphorylates and activates the new substrate lysine acetyltransferase 5 (KAT5), which acetylates HSL. We further show that acetylation licenses HSL to be phosphorylated for activation by PKA. After undergoing both acetylation and phosphorylation, HSL translocates to lipid droplets through binding to the lipid droplet protein perilipin 1 (PLIN1). In vivo , BAT-specific knockout of Kat5 severely impairs cold-induced lipolysis and thermogenesis in mice; re-introduction of wild-type KAT5, but not a PKA-unphosphorylatable mutant (KAT5 ^S86A ), rescues this defect. Strikingly, thermogenesis is also restored by an acetylation-mimetic HSL mutant (HSL ^2KQ ), but not by an acetylation-defective mutant (HSL ^2KR ), reassuring the critical role of the acetylation on HSL. Together, our findings elucidate a PKA-KAT5-HSL signaling pathway, in which KAT5-mediated acetylation acts as a mandatory amplifier, enabling HSL phosphorylation and subsequent the rapid lipolysis required for robust thermogenesis. Our work hence provides a comprehensive understanding of how cold-stimulated adrenergic signaling promotes lipid mobilization to fuel heat production.