Inflammation Regulation in Obese Patients

Overview

Insulin resistance is one of the main mechanisms involved in metabolic diseases. inflammation has been implicated in its pathogenesis, due to innate immunity activation by free fatty acids, lipopolysaccharides (LPS) and lactate. Free fatty acids, LPS and lactate activate innate immunity in squelettal muscle and adipose tissue via Toll-like receptor 2/4, NFkB, IRF3 (Interferon Responsive Factor 3) and cytokines secretion (TNFa, IFN g, IL1b, IL6), chemokines secretion (MCP1) and leukotrienes (LTB4). Feed back mechanisms involved in TLR signaling pathways as RLI (ribonuclease L inhibitor)/ABCE1, have never been studied in inflammation due to obesity. RLI inhibits an endoribonuclease, RNase L, which has been recently implicated in TLR signaling The purpose of this study is to analyse the role of RLI and RNase L in TLR regulation, and its potential implication in the link between obesity, inflammation and insulin resistance in adipose tissue and squeletal muscle in humans.

The investigators working hypothesis is that RNase L and RLI contribute to chronic inflammation regulation and to insulin response through TLR 4 pathway regulation in obesity. The investigators main purpose is to compare innate immunity activation pathway between insulin sensitive, insulin resistant obese patients and control patients. Insulin sensitive and insulin resistant obese patients will be distinguish thanks to the HOMA ir index. The investigators second objectives are to evaluate if the degree of inflammation in adipose tissue and squeletal muscle is correlated to insulin sensitivity measured by hyperinsulinemic euglycemic clamp and to characterise inflammatory pathway and regulation pathway. A special focus will be given to the leukotrienes and their potential role in insulin resistance pathogenesis. The investigators will have two approaches:- characterisation of subjects with normal weight, of obese insulin sensitive and obese insulin resistant through a metabolic evaluation, an inflammatory characterisation and a measure of insulin sensitivity at the systemic level, in adipose tissue and in squeletal muscle.- an in vitron approach with human myoblast and adipocytes culture, extracted from the investigators patients: characterisation of inflammation, innate immunity.