Abstract Calcium signaling is essential for adipocyte function; however, the upstream Ca 2+ channels coordinating adipose metabolism remain poorly defined. Here, we identify TRPC6 as a Ca 2+ channel enriched in early adipocyte progenitors that orchestrate white adipose tissue (WAT) homeostasis by integrating cAMP signaling and mitochondrial bioenergetics. In Trpc6 knockout mice, WAT emerges as the earliest and most vulnerable site of dysfunction, exhibiting pathological hypertrophic lipid accumulation despite impaired adipogenesis and intact hypothalamic signaling. Mechanistically, TRPC6 deficiency disrupts cAMP-hormone-sensitive lipase signaling and impairs mitochondrial oxidative metabolism, processes sustained by a reciprocal TRPC6–cAMP feedback loop. TRPC6 is transiently expressed during early adipogenic commitment and is indispensable for proper progenitor differentiation and lipid turnover. These findings define TRPC6 as a molecular gatekeeper that links Ca 2+ and cAMP signaling to mitochondrial metabolism, ensuring adipocyte plasticity and energy balance. Moreover, our study reveals a previously unrecognized mechanism that underlies WAT vulnerability to metabolic dysfunction and highlights the therapeutic potential of the TRPC6–cAMP–mitochondrial axis in obesity and insulin resistance.
Nguyen et al. (Fri,) studied this question.