Functional heterogeneity of POMC neurons relies on mTORC1 signaling.

DOI: http://doi.org/10.1016/j.celrep.2021.109800 Journal: Cell Rep E-pub date: 12 Oct 2021 Authors: N Saucisse, W Mazier, V Simon, E Binder, C Catania, L Bellocchio, RA Romanov, S Léon, I Matias, P Zizzari, C Quarta, A Cannich, K Meece, D Gonzales, S Clark, JM Becker, GSH Yeo, X Fioramonti, FT Merkle, SL Wardlaw, T Harkany, F Massa, G Marsicano, D Cota

Functional heterogeneity of POMC neurons relies on mTORC1 signaling.

Abstract:

Hypothalamic pro-opiomelanocortin (POMC) neurons are known to trigger satiety. However, these neuronal cells encompass heterogeneous subpopulations that release γ-aminobutyric acid (GABA), glutamate, or both neurotransmitters, whose functions are poorly defined. Using conditional mutagenesis and chemogenetics, we show that blockade of the energy sensor mechanistic target of rapamycin complex 1 (mTORC1) in POMC neurons causes hyperphagia by mimicking a cellular negative energy state. This is associated with decreased POMC-derived anorexigenic α-melanocyte-stimulating hormone and recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Electrophysiology and optogenetic studies further reveal that pharmacological blockade of mTORC1 simultaneously activates POMC/GABAergic neurons and inhibits POMC/glutamatergic ones, implying that the functional specificity of these subpopulations relies on mTORC1 activity. Finally, POMC neurons with different neurotransmitter profiles possess specific molecular signatures and spatial distribution. Altogether, these findings suggest that mTORC1 orchestrates the activity of distinct POMC neurons subpopulations to regulate feeding behavior.