Accelerated Aging of the Cells of Visceral Adipose Tissue in Morbid Obese Subjects

Overview

Numerous epidemiological studies clearly showed the relationship between the excessive growth of visceral adipose tissue and risk of developing insulin resistance, type 2 diabetes and other cardiovascular risk factors. However, the mechanisms contributing to the deleterious role of visceral adipose tissue remain to be elucidated. Several observations suggest that adipose tissue depots exhibit distinct metabolic and secretory capacities according to their locations. We have recently shown that visceral fat depots display higher immuno-inflammatory cells infiltration than that of subcutaneous fat. In addition, the endothelial cells of visceral compared to subcutaneous adipose tissues express a pro-inflammatory phenotype and several markers related to aging. Finally, we have shown that visceral adipocyte-derived secretions promote the endothelial cell senescence in an extent higher than subcutaneous adipocyte-derived products. These data suggest that senescence 1) might be a phenomenon related to the location and therefore the microenvironment of adipose tissue and 2) might be responsible for an abnormal activation of proinflammatory response, favouring the development of metabolic and secretory dysfunction of adipose tissue in obesity. Our working hypothesis, based on these observations, is that the visceral adipose tissue provides a microenvironment that promotes accelerated aging. This senescence may be responsible for the establishment of an inflammatory reaction, alteration of the metabolic activity and adipocyte differentiation capacity of progenitor cells leading to the development of obesity associated diseases. The proposed project is a descriptive cross-sectional pathophysiological study .The aims are 1) to better define the process of senescence in human adipose tissue, 2) to precise the mechanisms and 3) to analyse the cellular and functional consequences of aging on inflammation, adipose tissue development and metabolism. 200 morbidly obese candidates for bariatric surgery will be studied. The collection of clinical and laboratory data and the collection of biological samples (plasma, blood cells and subcutaneous and visceral adipose tissues) will be made at the inclusion and during surgery (obesity center, Hôpital Louis Mourier). Analyses of adipose tissue will be performed at INSERM U1048 and will focus on in vitro approaches of the cells of the adipose tissues (mature adipocytes, endothelial cells, progenitor cells and immuno-inflammatory cells). This project will permit to better understand the pathogenicity associated with the excessive growth of visceral adipose tissue and may reveal new therapeutic targets to limit obesity-associated pathologies.

Main objective: The main objectives are 1) to compare the state of senescence of subcutaneous versus visceral adipose tissues and 2) to define the senescent cell populations in subcutaneous and visceral adipose tissues in morbidly obese patients. Secondary objectives: Secondary objectives are 1) to precise whether the state of senescence is attributable to microenvironment, 2) to determine the impact of aging on cellular function, 3) to establish a link between the state of senescence of subcutaneous and visceral adipose tissues and obesity-associated pathologies.