Role of Cholesterol accumulation in White Adipose Tissue dysfunction – ChoWAT

White adipose tissue dysfunction is central to the development of obesity-associated complications such as type 2 diabetes, non-alcoholic fatty liver disease and cardiovascular diseases. Despite the importance of this tissue, little is known about the early molecular determinants contributing to the adipocyte dysfunction during obesity. Our hypothesis is that cholesterol is a major player in adipocyte dysfunction. Our preliminary results in cell and mouse models and in patients with obesity show the involvement of free cholesterol accumulation in the establishment of this dysfunction. They also suggest that cholesterol esterification with monounsaturated fatty acids could preserve adipose homeostasis. Using complementary approaches combining cellular and mouse preclinical models, as well as human samples, we propose to determine: 1/ how cholesterol is harmful to the adipocyte, 2/ the importance of its esterification in the maintenance of adipocyte homeostasis, and 3/ whether induction of its esterification by nutritional approaches preserves adipocyte function during obesity. This project will identify therapeutic targets and provide the proof of concept of the feasibility of a strategy to prevent the metabolic complications of obesity.