mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptin.

Magalie Haissaguerre, Amandine Ferrière, Vincent Simon, Nicolas Saucisse, Nathalie Dupuy, Caroline André, Samantha Clark, Omar Guzman-Quevedo, Antoine Tabarin, Daniela Cota
Molecular Metabolism. 2018-06-01; 12: 98-106
DOI: 10.1016/j.molmet.2018.04.002

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1. Mol Metab. 2018 Jun;12:98-106. doi: 10.1016/j.molmet.2018.04.002. Epub 2018 Apr
13.

mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food
intake and action of leptin.

Haissaguerre M(1), Ferrière A(1), Simon V(2), Saucisse N(2), Dupuy N(2), André
C(2), Clark S(2), Guzman-Quevedo O(2), Tabarin A(1), Cota D(3).

Author information:
(1)INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale,
U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie,
Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France;
Department of Endocrinology, Hôpital Haut Lévèque, CHU Bordeaux, F-33600 Pessac,
France.
(2)INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale,
U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie,
Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France.
(3)INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale,
U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie,
Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France.
Electronic address: .

OBJECTIVE: Nutrient availability modulates reactive oxygen species (ROS)
production in the hypothalamus. In turn, ROS regulate hypothalamic neuronal
activity and feeding behavior. The mechanistic target of rapamycin complex 1
(mTORC1) pathway is an important cellular integrator of the action of nutrients
and hormones. Here we tested the hypothesis that modulation of mTORC1 activity,
particularly in Proopiomelanocortin (POMC)-expressing neurons, mediates the
cellular and behavioral effects of ROS.
METHODS: C57BL/6J mice or controls and their knockout (KO) littermates deficient
either for the mTORC1 downstream target 70-kDa ribosomal protein S6 kinase 1
(S6K1) or for the mTORC1 component Rptor specifically in POMC neurons
(POMC-rptor-KO) were treated with an intracerebroventricular (icv) injection of
the ROS hydrogen peroxide (H2O2) or the ROS scavenger honokiol, alone or,
respectively, in combination with the mTORC1 inhibitor rapamycin or the mTORC1
activator leptin. Oxidant-related signal in POMC neurons was assessed using
dihydroethidium (DHE) fluorescence.
RESULTS: Icv administration of H2O2 decreased food intake, while
co-administration of rapamycin, whole-body deletion of S6K1, or deletion of rptor
in POMC neurons impeded the anorectic action of H2O2. H2O2 also increased oxidant
levels in POMC neurons, an effect that hinged on functional mTORC1 in these
neurons. Finally, scavenging ROS prevented the hypophagic action of leptin, which
in turn required mTORC1 to increase oxidant levels in POMC neurons and to inhibit
food intake.
CONCLUSIONS: Our results demonstrate that ROS and leptin require mTORC1 pathway
activity in POMC neurons to increase oxidant levels in POMC neurons and
consequently decrease food intake.

Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

DOI: 10.1016/j.molmet.2018.04.002
PMCID: PMC6001919
PMID: 29699927


Auteurs Bordeaux Neurocampus