Novel Function of TREK-1 in Regulating Adipocyte Differentiation and Lipid Accumulation

K2P (two-pore domain potassium) channels, a diversified class of K ⁺ -selective ion channels, have been found to affect a wide range of physiological processes in the body. Despite their established significance in regulating proliferation and differentiation in multiple cell types, K2P channels' specific role in adipogenic differentiation (adipogenesis) remains poorly understood. In this study, we investigated the engagement of K2P channels, specifically KCNK2 (also known as TREK-1), in adipogenesis using primary cultured adipocytes and TREK-1 knockout (KO) mice. Our findings showed that TREK-1 expression in adipocytes decreases substantially during adipogenesis. This typically causes an increased Ca ²⁺ influx and alters the electrical potential of the cell membrane. Furthermore, we observed a reduction in differentiation and lipid accumulation in both 3T3-L1 cell lines and primary cultured adipocytes when the TREK-1 activity was blocked with Spadin, the specific inhibitors, and TREK-1 shRNA. Finally, our findings revealed that mice lacking TREK-1 gained more weight and had worse glucose tolerance when fed a high-fat diet (HFD) compared to the wild-type controls. These findings imply that TREK-1 plays an important role in the control of adipogenesis and could be a potential target for the development of therapeutic treatments for obesity.