Functional heterogeneity of POMC neurons relies on mTORC1 signaling
Cell Reports. 2021-10-01; 37(2): 109800
DOI: 10.1016/j.celrep.2021.109800
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Saucisse N(1), Mazier W(1), Simon V(1), Binder E(1), Catania C(1), Bellocchio L(1), Romanov RA(2), Léon S(1), Matias I(1), Zizzari P(1), Quarta C(1), Cannich A(1), Meece K(3), Gonzales D(1), Clark S(1), Becker JM(4), Yeo GSH(4), Fioramonti X(5), Merkle FT(6), Wardlaw SL(3), Harkany T(7), Massa F(1), Marsicano G(1), Cota D(8).
Author information:
(1)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France.
(2)Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.
(3)Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
(4)Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
(5)NutriNeuro, UMR 1286 INRAE, Bordeaux University, Bordeaux INP, F-33000 Bordeaux, France.
(6)Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK; Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK.
(7)Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria; Department of Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden.
(8)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France. Electronic address: .
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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement: Declaration of interests The authors declare no competing interests.