OBERSTRESS · Hypothalamic Lipotoxicity and Endoplasmic Reticulum Stress: a New Pathophysiological Mechanism of Obesity

It is well established that metabolically relevant organs such as adipose tissue, pancreatic beta cells, liver and skeletal muscle develop endoplasmic reticulum (ER) stress under conditions of obesity induced lipotoxicity. Here, the applicant will investigate if/how the hypothalamus is affected by lipotoxicity and ER stress in the context of obesity* Scientific Hypotheses:1. Obesity is associated with lipotoxicity and ER stress in the hypothalamus.2. Hypothalamic ER stress may contribute to the development of obesity through dysregulation of the mechanisms controlling energy balance.3. Based on our preliminary data, we hypothesize that CHOP, a mediator of ER stress, could be a key modulator of the association between obesity and ER dysfunction in the hypothalamus.* General Objective: to determine the relevance of hypothalamic lipotoxicity and ER stress for the development of obesity and whether targeting ER stress mechanisms is a successful therapeutic strategy to prevent or revert obesity and its metabolic complications.* Specific Objectives:1. To determine whether obesity and the metabolic syndrome are associated with hypothalamic lipotoxicity, ER stress and whether these effects are hypothalamic nuclei specific2. To determine whether primary hypothalamic ER stress is a cause of altered energy balance leading to obesity and metabolic complications3. To determine whether in the context of obesity inhibition of ER stress in hypothalamus affects energy balance and obesity associated metabolic complications4. To determine the role of CHOP on energy balance and obesity in specific hypothalamic neuronal populationsThis project is central to the applicant’s goal of understanding how the hypothalamus regulates energy balance under physiological and pathophysiological conditions, as an essential step towards identifying and developing novel molecular drug targets to tackle the problem of obesity and their metabolic complications.