Adipose tissue fibrosis : local and clinical consequences in obesity – adipofib

Chronic inflammation of white adipose tissue (WAT), more important in visceral than in subcutaneous WAT, is thought to contribute to local and systemic co-morbidities of obesity. We recently revealed fibrosis as a new player in WAT biology and its alteration in obese subjects. Our general objective is to investigate the pathophysiological consequences of fibrosis in human subcutaneous and visceral WAT during obesity, in relation with chronic inflammation. For this purpose, we want to 1) identify the molecular and cellular actors of peri-adipocyte fibrosis and the functional impact exerted on adipocyte metabolism; 2) explore the clinical consequences of WAT fibrosis in large cohorts through the development of non-invasive measurements of subcutaneous WAT fibrosis. We will combine a clinical study with investigations on cellular models to evaluate the metabolic consequences of fibrosis and its relevance as a predictor of weight loss intervention outcome. This translational approach will allow us to bring new knowledge on relationship between chronic inflammation and WAT remodelling in human obesity. Four tasks (T) have been defined as follow:
T1: organisation and coordination of the project
T2: To define the contributing role of molecular actors and adipocytes in pericellular fibrosis deposition. To examine the production of fibrotic proteins by mature adipocytes in response to pro- or anti-inflammatory macrophages. To consider Inhibin beta A as a potential candidate and find new molecular actors by combining proteomic and transcriptomic approaches.
T3: To use our original 3D-system of human adipocyte culture to study the influence of mechanical constraints on adipocyte biology. To get information on the transcriptomic signatures of “fibrotic” adipocytes. To investigate the putative contribution of new molecular pathways.
T4: To develop and validate a device based on the “vibration controlled transient elastography” dedicated to the measure of WAT stiffness. To explore the pathophysiological relevance of WAT fibrosis in large populations of obese subject before and after weight loss. To address the role of WAT fibrosis/stiffness as predictor of the outcome of weight loss in humans in response to caloric restriction.
Overall, our studies should provide breakthroughs in basic and biomedical researches with:
- The identification and contribution of molecular and cellular actors in the production of fibrotic components in human subcutaneous and visceral WAT.
- The demonstration that the fibrotic microenvironment present in obese WAT alters the metabolic capacities in “fibrotic” adipocytes by exerting mechanical constraints and related signalling pathways.
- The development of new non invasive tools (AdiposcanTM) to measure WAT stiffness/fibrosis.
- The identification of the pathophysiological consequences of WAT fibrosis on obesity metabolic complications and caloric restriction outcome.

We believe that this project will increase our knowledge of the physiopathology of fibrotic processes in WAT, before considering the future potential use of antifibrotic molecules to correct WAT alterations during obesity.