ANR CHoWat : Simon Ducheix (2022 - 2026)

Simon Ducheix is the scientific leader of the ANR funded project : Role of Cholesterol in White Adipose Tissue dysfunction

Abstract

Obesity is a major risk factor for cardiometabolic complications such as type 2 diabetes and cardiovascular diseases. Beyond white adipose tissue (WAT) mass, the healthy development of WAT is of major importance in the onset of these complications. The "WAT limit of expansion" hypothesis proposes that each individual has his own adipose storage capacity and, once it is exceeded, adipocytes become dysfunctional. Then, lipids will be deposited ectopically in different organs and thus will contribute to the development of insulin resistance through lipotoxicity-related mechanisms. Numerous studies focused on deciphering the mechanisms leading to WAT failure during obesity by determining the role of inflammation, fibrosis, hypoxia and altered lipid storage in the WAT. However, the early molecular events rendering adipocytes dysfunctional remain poorly understood. Cholesterol could be a molecular determinant triggering adipose dysfunction as it has been previously showed that :1/ WAT is the most important reservoir of total body cholesterol: from 25% in a healthy subject up to 50% in obese patients, and 2/ that supra-physiological dietary cholesterol supply leads to WAT dysfunction in mouse and in primate. However, we still do not know if adipose cholesterol accumulation triggers WAT dysfunction and how cholesterol would exert such deleterious effect.

Our preliminary data in patients with obesity and in mouse models show a positive correlation between free cholesterol content in adipose tissue and adipose dysfunction. Cellular studies then demonstrated the causal role of free cholesterol accumulation in the establishment of this dysfunction. Moreover, in vitro approaches also suggest that cholesterol esterification could preserve adipose homeostasis.

Objectives

Using complementary approaches combining cellular, murine preclinical models as well as human samples, we propose to determine: 1/ how free cholesterol accumulation deregulates adipocyte homeostasis, 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.