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

Authors: SCHAAR, ANNE - University Of North Dakota; SUN, YUYANG - University Of North Dakota; ROSENBERGER, THAD - University Of North Dakota; Krout, Danielle; Roemmich, James; BRINBAUMER, LUTZ - National Institutes Of Health (NIH); Larson, Kate; SINGH, BRIJ - University Of North Dakota

Submitted to: Journal of Cell Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/27/2019
Publication Date: 6/10/2019
Citation: Schaar, A., Sun, Y., Rosenberger, T.A., Krout, D.P., Roemmich, J.N., Brinbaumer, L., Larson, K.J., Singh, B. 2019. Calcium entry via TRPC1 is essential for cellular differentiation and modulates secretion via the SNARE complex. Journal of Cell Science. https://doi.org/10.1242/jcs.231878.
DOI: https://doi.org/10.1242/jcs.231878

Interpretive Summary: One way that fat cells play an important role in obesity-associated chronic diseases is by how promptly they mature to increase body fatness and by the types and amounts of hormones, called adipokines, that they secrete. In this study, we provide evidence that regulation of fat cell calcium concentration by calcium channels called TRPC1 plays an important role in fat cells mature their fat storing capacity and regulation of their energy metabolism. This has effects on body adiposity. Using TRPC1 gene deficient (knockout or KO) mice, we showed that mice without TRPC1 calcium channels have decreased adipocyte differentiation, reduced fat oxidation, increased fat accumulation in adipose tissue, decreased organ weight, and reduced blood concentrations of adipokine called adiponectin and a well known energy metabolism regulator leptin. It is particularly important that concentrations of adiponectin which is well known for increasing energy metabolism was reduced in TRPC1KO mice in blood, but not in fat tissue. We showed that a cellular regulator of adipokine export from fat cells called Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (or SNARE) were responsible for reducing adiponectin and leptin secretion from fat cells from TRPC1 KO mice. These results suggest that TRPC1 contributes to the adipocyte differentiation and provides a mechanism for adiponectin and leptin, indicating that TRPC1 has a vital role in the regulation of metabolic homeostasis by indirectly regulating secretion of these hormones from fat cells.

Technical Abstract: Adipocyte functionality, including adipocyte differentiation and adipokine secretion, is essential in obesity-associated metabolic syndrome. Here, we provide evidence that Ca2+ influx in primary adipocytes, especially upon 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 dependent on TRPC1-STIM1 and blocking Ca2+ entry with SKF-96365 or TRPC1-/- derived 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 adipocytes differentiation and adiponectin secretion, and loss of TRPC1 disturbs metabolic homeostasis.