Description du projet
La base neuronale de la gestion du poids
La reprise de poids après un régime est un phénomène courant appelé «effet yoyo». Comprendre les mécanismes responsables du maintien de la perte de poids s’avère donc important, notamment pour le traitement de l’obésité. Le projet Yoyo-LepReSens, financé par l’UE, se concentrera sur les mécanismes épigénétiques qui gouvernent la reprise de poids par la suralimentation. Les scientifiques étudieront l’épigénétique d’un sous-ensemble spécifique de neurones de l’hypothalamus et déchiffreront comment ils sont impliqués dans la gestion du poids. En outre, le projet examinera l’émergence de la résistance à la leptine, une hormone connue pour son rôle dans la régulation de la satiété. Les résultats constitueront la base pour la conception d’interventions innovantes destinées à lutter contre l’obésité.
Objectif
Obesity and its comorbid sequelae are major health burdens across European nations. Many citizens would greatly benefit from permanent weight loss, but only a few succeed. They rather suffer from weight regain after dieting, often referred to as Yoyo effect. Delineating the largely unexplored, CNS-driven molecular events that impede sustainable weight loss and drive the Yoyo effect is a prerequisite for future therapies, and a major goal of my proposal.
Recently, my lab demonstrated unprecedented weight loss in diet-induced obese mice treated with the plant-derived leptin sensitizer celastrol. Our data suggested breakthrough potential for therapeutic anti-obesity strategies built upon leptin re-sensitization, and pointed towards a key role for orexigenic circuitry and AgRP neurons residing in the hypothalamic arcuate nucleus. As 1st objective, we will 1) establish if leptin resistance originates in AgRP neurons, 2) delineate the molecular underpinnings of leptin resistance and leptin resensitization in AgRP neurons, 3) verify novel drug-able leptin signalling components in murine and human iPSC-derived cells and 4) identify leptin sensitizing weight loss drugs.
AgRP neurons will also be in the focus of my 2nd objective that targets epigenetic mechanisms of Yoyo dieting. Building upon our own data on epigenetic mechanisms that drive weight re-gain through hyperphagia, we will 1) establish if an epigenetic memory for obesity in AgRP neurons exists, 2) explore by Crispr-Cas9-based trans-epigenetic modulation of AgRP neurons in mice whether resetting the epigenetic memory for obesity can prevent weight regain and 3) demonstrate the human relevance of our new weight regulatory genes in post-mortem human hypothalami of lean, obese or type 2 diabetic donors.
Overall, my proposal will establish hypothalamic AgRP neurons as crucial drivers for leptin resistance and Yoyo dieting. My translational aims are further providing the groundwork for future anti-obesity therapeutics.
Champ scientifique
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
85764 Neuherberg
Allemagne