Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss

Anthony H. K. Tsang; Nicholas Heeley; Constanza Alcaino; Eun‐Sang Hwang; Brian Lam; Taufiq Rahman; Tamana Darwish; Danaé Nuzzaci; Richard G. Kay; Amar Sarkar; Ruiyan Wang; Nihal Basha; Austin Punnoose; Peter Kirwan; Marcella K.L. Ma; Giles S.H. Yeo; Florian T. Merkle; Fiona M. Gribble; Frank M. Reimann; Kevin William; Clémence Blouet

doi:10.1101/2024.09.13.612843

NeurosciencebioRxivSep 13, 2024

Preprint

Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss

Anthony H. K. Tsang iD, Nicholas Heeley, Constanza Alcaino iD, Eun‐Sang Hwang iD, Brian Lam iD, Taufiq Rahman iD, Tamana Darwish, Danaé Nuzzaci, Richard G. Kay iD, Amar Sarkar iD, Ruiyan Wang iD, Nihal Basha iD, Austin Punnoose, Peter Kirwan iD, Marcella K.L. Ma iD, Giles S.H. Yeo iD, Florian T. Merkle iD, Fiona M. Gribble iD, Frank M. Reimann iD, Kevin William, Clémence Blouet iD

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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