Functional heterogeneity of POMC neurons relies on mTORC1 signaling.
Romanov, Roman A
Becker, Julia M
Yeo, Giles SH
Wardlaw, Sharon L
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Saucisse, N., Mazier, W., Simon, V., Binder, E., Catania, C., Bellocchio, L., Romanov, R. A., et al. (2021). Functional heterogeneity of POMC neurons relies on mTORC1 signaling.. Cell Rep, 37 (2. ARTN 109800), 109800. https://doi.org/10.1016/j.celrep.2021.109800
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.
CB(1) receptor, Endocannabinoid, Food intake, GABA, Glutamate, Melanocortin, POMC neuron, mTOR
Wellcome Trust (211221/Z/18/Z)
Medical Research Council (MC_UU_12012/1)
Medical Research Council (MC_UU_12012/5)
External DOI: https://doi.org/10.1016/j.celrep.2021.109800
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332252
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/