Obesity is a multifactorial disease reflecting complex interactions among genetic, environmental and behavioral factors such as high-energy diets and physical inactivity. The global increase in obesity is such that it is considered today as “pandemic”. France is no exception to this situation with 33% of the adult population overweight (based on calculation of Body Mass Index: weight / height2; 25 kg / m2 ≤ BMI ≤ 30 kg / m2) and 15% obese (BMI > 30 kg / m2 ).Global numbers of overweight and obese adults are projected to reach 2.16 billion and 1.12 billion by 2030. Obesity has a significant impact on health by promoting the occurrence of chronic disorders including notably type 2 diabetes (T2D), cardiovascular diseases and cancers. One key feature in the metabolic complications of obesity is the development of insulin resistance (IR), which occurs several years before the onset of T2D. Interestingly, approximately 30% of the obese individuals never develop IR and T2D. However, the mechanisms enabling the preservation of insulin sensitivity in these obese individuals remain largely elusive.
It is now well established that obesity is associated with chronic low-grade inflammation and oxidative stress, both contributing to impair insulin sensitivity in peripheral tissues such as skeletal muscle and adipose tissue.
Free fatty acids (FFA) and lipopolysaccharides (LPS), two lipid species found at elevated plasma levels in obese people, have been identified as inducers of these deleterious processes. They activate the toll like receptors 4 (TLR4), which leads to oxidative stress, local activation of the innate immune response and the production and release of inflammatory cytokines. Innate immunity, inflammation and oxidative stress are normally finely controlled by the induction of negative regulators to avoid unchecked and deleterious reactions. Type I interferons (IFNI) play an important role in the balance between activation and inhibition of the immune response. In the same way, pro-oxidants are naturally neutralized or detoxified by enzymes such as superoxide dismutases (SOD) or natural compounds as polyphenols (PPs).
Our objective is to investigate the regulation of immune and oxidative pathways and their possible involvement in the relationship between obesity, micro-inflammation, oxidative stress and IR in human’s adipose tissue and skeletal muscle. We are developing a translational research approach in collaboration with the departments of Clinical Physiology, Nutrition, Diabetes, Biochemistry and Clinical Investigation Center (CIC) of the University Hospital of Montpellier (See Figure 1).
We have recently shown that a natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR in first-degree relatives of T2D patients (Hokayem et al, 2013). We have identified a defect in the innate immune response and more particularly to type 1 interferons (IFN1 / IFNa / β) in muscle cells of insulin resistant obese subjects, leading to down-regulation of MnSOD expression (Fabre et al, 2014, Patent INSERM Transfert).
Our objectives :
- Analysis of the molecular mechanisms that regulate TLR4 pathway and mitochondrial anti-oxidative response in human muscle and adipose tissue during obesity.
- Develop, from the above identified mechanisms, treatments that allow insulin sensitivity maintaining during obesity.
Figure 1 : Schematic drawing of our translational research project
- Olivier Birot (York University, Toronto, Canada).
- Magnus Bäck (Karolinska University Hospital, Stockholm, Suéde).
- Cédric Moro (Inserm/UPS UMR 1048 – I2MC, Toulouse).
Financial Support :
- University of Montpellier
- SFD (Société Francophone du Diabète)
- AOI CHRU Montpellier
Major Publication :
- 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.