Journal
CELL REPORTS
Volume 37, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109800
Keywords
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Categories
Funding
- INSERM
- Labex Brain
- Aquitaine Region
- ANR [ANR-13-BSV4-0006, ANR-18-CE140029 MitObesity, Labex BRAIN ANR-10-LABX-43, ANR-20101414-01, ANR-10-EQX-008-1 OPTOPATH, ANR-17-CE14-0007 BABrain, ANR-16-CE37-0010, ANR-20-CE14-0046]
- FFRD
- INSERM/Aquitaine Region PhD fellowship
- FRM PhD fellowship [FDT20150532545, FDT201805005371]
- FrenchMinistry for Higher Education, Research and Innovation
- French Ministry for Higher Education, Research and Innovation
- French Society of Endocrinology (SFE)
- French Society of Nutrition (SFN)
- French Society of Diabetes (SFD)
- European Commission [224757, HEALTH-F2-2008-223713, HEALTH-603191 FP7-People2009-IEF-251494, ERC-2010-StG-260515, ERC-2014-PoC640923]
- FRM
- Postgraduate Scholarship Programme of the Free State of Saxony and Erasmus Traineeship Programme
- Medical Research Council [MR/P501967/1]
- Wellcome Trust
- Royal Society [211221/Z/18/Z]
- NIH [DK080003]
- Swedish Research Council
- Hjarnfonden
- Novo Nordisk Foundation
- ERC SECRETCELLS
- Medical University of Vienna
- EMBO [ALTF 596-2014]
- Marie Curie Actions EMBOCOFUND2012 [GA-2012-600394]
- Wellcome Trust [211221/Z/18/Z] Funding Source: Wellcome Trust
- Agence Nationale de la Recherche (ANR) [ANR-17-CE14-0007, ANR-20-CE14-0046, ANR-16-CE37-0010] Funding Source: Agence Nationale de la Recherche (ANR)
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Blocking the energy sensor mTORC1 in POMC neurons can mimic a cellular negative energy state, leading to hyperphagia. The functional specificity of the GABA and glutamate subpopulations in POMC neurons relies on the activity of mTORC1.
Hypothalamic pro-opiomelanocortin (POMC) neurons are known to trigger satiety. However, these neuronal cells encompass heterogeneous subpopulations that release gamma-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 a-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.
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