TRPC6 governs brown adipose thermogenesis via a BMPR2-p38 MAPK signaling axis

Brown adipose tissue (BAT) thermogenesis combats obesity, but mechanisms linking calcium dynamics to thermogenic programming remain incompletely defined. Here, we identify the calcium channel TRPC6 as an essential BAT-intrinsic regulator of metabolic health. BAT-specific Trpc6 knockout (Trpc6^BTKO) mice exhibit spontaneous BAT whitening, mitochondrial dysfunction, and impaired cold tolerance. Upon high-fat diet (HFD) challenge, Trpc6^BTKO mice develop exacerbated obesity, hepatic steatosis, and insulin resistance. These phenotypes are driven by increased energy intake and reduced energy expenditure associated with impaired thermogenesis. TRPC6 deficiency suppresses mitochondrial biogenesis and thermogenesis. Mechanistically, TRPC6 mediates calcium influx and interacts directly with BMPR2, thereby selectively activating p38 MAPK signaling to drive thermogenic gene expression. Genetic disruption of the TRPC6-BMPR2 complex abolishes TRPC6-mediated thermogenesis. Thus, we define a non-redundant TRPC6-BMPR2-p38 MAPK signaling axis whose disruption underpins obesity and associated metabolic dysfunction, positioning it as a promising therapeutic target for metabolic disease.