Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss
Tsang, A. H.; Heeley, N.; Alcaino, C.; Hwang, E.; Lam, B. Y.; Rahman, T.; Darwish, T.; Nuzzaci, D.; Kay, R. G.; Sarkar, A.; Wang, R.; Basha, N.; Punnoose, A.; Kirwan, P.; Ma, M.; Yeo, G. S.; Merkle, F. T.; Gribble, F. M.; Reinmann, F.; Williams, K.; Blouet, C.
Show abstract
Hypothalamic leucine sensing promotes satiety and weight loss but an understanding of how leucine regulates neuronal activity is lacking. Here we show that Cacna1g, encoding the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of POMC neurons as well as the anorectic response to leucine in vivo. In addition, genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, we show that leucine binds to the voltage-sensing segment of Cav3.1, thereby reducing its threshold for voltage-dependent activation. Last, pharmacological activation of hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates the weight loss response to GLP-1 receptor agonism. These results reveal that Cav3.1 is a neuronal leucine sensor and a relevant weight loss target.
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