Nicolas Saucisse

Dissecting the role of the intacellular mTORC1 pathway in hypothalamic melanocortin circuitry regulating food intake

Defended: December 6, 2016

PhD supervisor : Daniela Cota, MD, HDR  Group Leader, Group “Energy Balance and Obesity” / INSERM U1215, Université de Bordeaux  / NeuroCentre Magendie 

The hypothalamus is a brain structure with a key role in the regulation of food intake. Among the different neuronal populations of which it is composed, pro-opio-melanocortin (POMC) neurons are classically known to decrease food intake and body weight through the release of neuropeptides produced by the cleavage of POMC. Our study, through the use of genetic, pharmacological, electrophysiological and molecular approaches, challenges conventional notions about POMC neuron function in energy balance by showing that there are two functionally distinct POMC neuronal sub-populations, which increase or decrease food intake depending on which neurotransmitter they release, γ-aminobutyric acid (GABA) or glutamate. A third population capable of producing both GABA and glutamate has also been identified. The regulation of POMC GABAergic and glutamatergic neurons depends on the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which functions as a cellular energy sensor, and the endocannabinoid system (ECS), which regulates neurotransmitters release. In addition, we have also demonstrated through the use of a conditional knockout mice, the importance of the protein p62 or sequestrome 1 (p62/SQSTM1), which regulates mTORC1 activity and autophagy, in POMC neurons for the regulation of energy homeostasis. Our data provide new insights on the molecular mechanisms involved in the regulation of energy balance.

Key words: POMC neurons, mTORC1, ECS, neurotransmitters, food intake, refeeding, p62/SQSTM1, metabolism, hypothalamus, obesity

 

Publications 

Delpech JC, SAUCISSE N, Parkes SL, Lacabanne C, Aubert A, Casenave F, Coutureau E, Sans N, Layé S, Ferreira G & Nadjar A. Microglial activation enhances associative taste memory through purinergic modulation of glutamatergic neurotransmission. The Journal of Neuroscience, 2015 Feb; 35(7):3022-3033.

Haissaguerre M*, SAUCISSE N* & Cota D. Influence of mTOR in energy and metabolic homeostasis. Molecular and Cellular Endocrinology. 2014 Nov; 397(1-2):67-77. *Equally contributing (revue).

Mazier W*, SAUCISSE N*, Gatta-Cherifi B & Cota D. The Endocannabinoid System: Pivotal Orchestrator of Obesity and Metabolic Disease. Trends in Endocrinology & Metabolism. 2015 Oct; 26(10):524-37. *Equally contributing (revue).

SAUCISSE N*, Mazier W*, Catania C, Binder E, Bellocchio L, Romanov RA, Cannich A, Simon V, Matias I, Meece K, Gonzales D, Clark S, Wardlaw SL, Harkany T, Massa F, Marsicano G & Cota D. mTORC1 and CB1R signaling control two POMC neurons subpopulations that oppositely drive feeding. Submitted 2016 *Equally contributing.

SAUCISSE N*, Simon V*, Gonzales D, Clark S, Moscat, J & Cota D. Disruption of autophagy in POMC neurons alters energy balance and impairs both mTOR/STAT3 signaling pathways and POMC neuronal morphology. In preparation *Equally contributing.


Jury

Guillaume Ferreira,
DR, INRA UMR 1286, Université de Bordeaux

Président

Alexandre Benani,
CR, CNRS-INRA UMR 6265, Université de Bourgogne

Rapporteur

Serge Luquet,
DR, CNRS UMR 8251, Université Paris Diderot-Paris 7,

Rapporteur

Philippe Ciofi,
CR, INSERM U1215, Université de Bordeaux,

Examinateur

 Uberto Pagotto,
PU, Université de Bologne, Italie

Examinateur

Daniela Cota,
CR, INSERM U1215, Université de Bordeaux,

Directeur de thèse

PhD supervisor


Daniela Cota
Group leader: Team ‘Energy balance and obesity’, : Daniela Cota, MD.
Publications PubMed

Obesity is a major health problem worldwide. However, despite the human and economic costs of this disease, efficient anti-obesity therapies are currently lacking….more

 

Last update: 4 April 2018