BK channel deficiency promotes lipolysis via an AKT-independent activation of the cAMP/PKA/HSL pathway.

Adipocyte lipolysis mobilizes stored triglycerides during energy deprivation, a process tightly regulated to maintain metabolic homeostasis. The large conductance calcium-activated potassium channel (BK) is present in adipocytes and is involved in intracellular lipid metabolism. This study aims to investigate the role of BK in regulating adipocyte lipolysis. Using BK knockout (BK-KO) rats, adipocyte-specific BK knockout (BKadipo-/-) mice, and in vitro differentiated adipocytes, we demonstrate that BK channel deficiency promotes lipolysis. We found that deletion of BK channels attenuated body weight gain accompanied by upregulation of the lipolysis pathway. BKadipo-/- mice fed a high-fat diet (HFD) showed attenuated weight gain, reduced adipocyte hypertrophy, and improved insulin sensitivity. Meanwhile, BK deletion enhanced lipolysis of mature adipocytes stimulated by CL-316243 compared with control cells. Mechanistically, BK deletion enhanced hormone-sensitive lipase (HSL) phosphorylation at Ser660 via an AKT-independent activation of the cAMP/PKA pathway while bypassing the inhibitory phosphorylation at Ser565. BK depletion facilitates lipolysis and attenuates diet-induced obesity via activating the cAMP/PKA/HSL pathway. These findings identify BK channels as critical negative regulators of adipocyte lipolysis, suggesting that targeting BK channels may represent a novel therapeutic strategy for obesity and related metabolic disorders.