<p>Calcium signaling is essential for adipocyte function; however, the upstream Ca²⁺ channels coordinating adipose metabolism remain poorly defined. Here, we identify TRPC6 as a Ca²⁺ channel enriched in early adipocyte progenitors that orchestrate white adipose tissue (WAT) homeostasis by integrating cAMP signaling and mitochondrial bioenergetics. In <i>Trpc6</i> 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 Ca²⁺ 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.</p>