In recent years the incidence of obesity and associated metabolic disorders has increased dramatically, and obesity is now considered a pandemic. In France, in 2014, 33% of the adult population is overweight [25 kg / m2 ≤ BMI (Body Mass Index: Weight / Height2) <30 kg / m2] and 15% is obese [BMI> 30 kg / m2 and 4 million people are diabetic. Obesity is associated with several health problems: insulin resistance (IR), type 2 diabetes (T2DM), hepatic steatosis and some cancers.
The development of IR is characterized by a decrease in insulin sensitivity of insulin-sensitive organs such as adipose tissue, liver, skeletal muscle, pancreas. This decrease is offset by increased insulin secretion by the pancreas to maintain glucose homeostasis. When this compensation is no longer assured the DT2 is declared. However, it is important to note that for about 30% of obese people, insulin sensitivity is preserved.
Numerous studies have shown a link between low grade chronic inflammation, obesity and IR. This inflammation is a consequence of the activation of innate immunity, in particular Toll Like Receptor 4 (TLR4), by free fatty acids (GLA) and bacterial lipopolysaccharides (LPS).
Our group, in collaboration with the departments of Clinical Physiology, Nutrition-Diabetes, Biochemistry and the Clinical Investigation Center (CIC) of the University Hospital of Montpellier, is developing a translational research project (Figure). We are interested in the molecular mechanisms that lead from the activation of TLR4 to the development of IR in humans as well as the identification of mechanisms that allow some obese subjects to keep their sensitivity to insulin, in order to identify new therapeutic targets and develop new treatments.
We have demonstrated a defect of the innate immune response and more particularly of type 1 interferons (IFN1 / IFNα / β) in the muscle cells of obese insulin-resistant subjects (Fabre et alCell Death and Disease,, 2014, Mar 20; 5: e1136, INSERM-Transfer patent).
Translational Research Strategy : Molecular mechanisms of IR and identification of therapeutic target
(Illustrated in french version)
Our goals :
- Understand in obese subjects the molecular mechanisms that regulate the activation of innate immunity and oxidative stress in two insulin-sensitive tissues, skeletal muscle and adipose tissue.
- Develop treatments to maintain insulin sensitivity in obese subjects.
- Olivier Birot (York University, Toronto, Canada).
- Magnus Bäck (Karolinska University Hospital, Stockholm, Suéde).
- Cédric Moro (Inserm/UPS UMR 1048 – I2MC, Toulouse).
Financial Supports :
- Université de Montpellier
- SFD (Société Francophone du Diabète)
- AOI CHRU Montpellier
- Fabre O, Breuker C, Amouzou C, Salehzada T, Kitzmann M, Mercier J, Bisbal C. (2014). “Defects in TLR3 expression and RNase L activation lead to decreased MnSOD expression and insulin resistance in muscle cells of obese people.” Cell Death Dis.;5:e1136..
- Bäck M, Avignon A, Stanke-Labesque F, Boegner C, Attalin V, Leprieur E, Sultan A.(2014).”Leukotriene production is increased in abdominal obesity. ” PLoS One. ;9(12):e104593.
- Hokayem M, Blond E, Vidal H, Lambert K, Meugnier E, Feillet-Coudray C, Coudray C, Pesenti S, Luyton C, Lambert-Porcheron S, Sauvinet V, Fedou C, Brun JF, Rieusset J, Bisbal C, Sultan A, Mercier J, Goudable J, Dupuy AM, Cristol JP, Laville M, Avignon A.(2013).” Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients. ”Diabetes Care. 36(6):1454-61.
- Fabre O, Salehzada T, Lambert K, Boo Seok Y, Zhou A, Mercier J, Bisbal C.(2012). “RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation.“ Cell Death Differ. 19(9):1470-81.
- Salehzada T, Cambier L, Vu Thi N, Manchon L, Regnier L, Bisbal C. (2014). “Endoribonuclease L (RNase L) regulates the myogenic and adipogenic potential of myogenic cells. “ PLoS One. 4(10):e7563.