Ca(2+) 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 Ca(2+) influx in primary adipocytes, especially upon Ca(2+) store depletion, plays an important role in adipocyte differentiation, functionality and subsequently metabolic regulation. The endogenous Ca(2+) entry channel in both subcutaneous and visceral adipocytes was found to be dependent on TRPC1–STIM1, and blocking Ca(2+) 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 Ca(2+) 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. This article has an associated First Person interview with the first author of the paper.