PT  - JOURNAL ARTICLE
AU  - Nicolas Saucisse
AU  - Wilfrid Mazier
AU  - Vincent Simon
AU  - Elke Binder
AU  - Caterina Catania
AU  - Luigi Bellocchio
AU  - Roman A. Romanov
AU  - Isabelle Matias
AU  - Philippe Zizzari
AU  - Stephane Leon
AU  - Carmelo Quarta
AU  - Astrid Cannich
AU  - Kana Meece
AU  - Delphine Gonzales
AU  - Samantha Clark
AU  - Julia M. Becker
AU  - Giles S.H. Yeo
AU  - Florian T. Merkle
AU  - Sharon L. Wardlaw
AU  - Tibor Harkany
AU  - Federico Massa
AU  - Giovanni Marsicano
AU  - Daniela Cota
TI  - POMC neurons functional heterogeneity relies on mTORC1 signaling
AID  - 10.1101/2020.03.25.007765
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.25.007765
4099  - http://biorxiv.org/content/early/2020/03/26/2020.03.25.007765.short
4100  - http://biorxiv.org/content/early/2020/03/26/2020.03.25.007765.full
AB  - Hypothalamic Pro-opiomelanocortin (POMC) neurons are classically known to trigger satiety. However, they encompass heterogeneous subpopulations whose functions are unknown. Here we show that POMC neurons releasing GABA, glutamate or both neurotransmitters possess distinct spatial distribution, molecular signatures and functions. Functional specificity of these subpopulations relies on the energy sensor mechanistic Target of Rapamycin Complex 1 (mTORC1), since pharmacological blockade of mTORC1, by mimicking a cellular negative energy state, simultaneously inhibited POMC/glutamatergic and activated POMC/GABAergic neurons. Chemogenetics and conditional deletion of mTORC1 then demonstrated that mTORC1 blockade in POMC neurons causes hyperphagia. This is due to decreased POMC-derived anorexigenic α-melanocyte-stimulating hormone and the recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Genetic inhibition of glutamate release from POMC neurons also produced hyperphagia, recapitulating the phenotype caused by mTORC1 blockade. Altogether, these findings pinpoint the molecular mechanisms engaged by POMC neurons to oppositely control feeding, thereby challenging conventional views about their functions.