Descripción del proyecto
La base neuronal del control de peso
Recuperar el peso perdido después de una dieta es un hecho común y se conoce como «efecto yoyó». Es importante comprender los mecanismos responsables de mantener el adelgazamiento, especialmente para el tratamiento de la obesidad. El proyecto Yoyo-LepReSens, financiado con fondos europeos, se centrará en los mecanismos epigenéticos que potencian la recuperación de peso al comer en exceso. Unos científicos estudiarán la epigenética de un subconjunto específico de neuronas en el hipotálamo y descifrarán cómo afectan el control del peso. Además, investigarán la aparición de la resistencia a la leptina, conocida por su papel en la regulación de la saciedad. Los resultados constituirán la base para el diseño de intervenciones nuevas para hacer frente a la obesidad.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
85764 Neuherberg
Alemania