Ca²⁺ entry via TRPC1 is essential for cellular differentiation and modulates secretion via the SNARE complex

Properties of adipocytes, including differentiation and adipokine secretion, are crucial factors in obesity-associated metabolic syndrome. Here, we provide evidence that Ca²⁺ influx in primary adipocytes, especially upon Ca²⁺ store depletion, plays an important role in adipocyte differentiation, functionality and subsequently metabolic regulation. The endogenous Ca²⁺ entry channel in both subcutaneous and visceral adipocytes was found to be dependent on TRPC1–STIM1, and blocking Ca²⁺ entry with SKF96365 or using TRPC1−/− knockdown adipocytes inhibited adipocyte differentiation. Additionally, TRPC1−/− mice have decreased organ weight, but increased adipose deposition and reduced serum adiponectin and leptin concentrations, without affecting total adipokine expression. Mechanistically, TRPC1-mediated Ca²⁺ entry regulated SNARE complex formation, and agonist-mediated secretion of adipokine-loaded vesicles was inhibited in TRPC1−/− adipose. These results suggest an unequivocal role of TRPC1 in adipocyte differentiation and adiponectin secretion, and that loss of TRPC1 disturbs metabolic homeostasis.