FTO is increased in muscle during type 2 diabetes and its over-expression in myotubes alters insulin signalling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction.
- Amélie Bravard1,2,3,4,5,
- Etienne Lefai1,2,3,4,5,
- Emmanuelle Meugnier1,2,3,4,5,
- Sandra Pesenti1,2,3,4,5,
- Emmanuel Disse5,
- Julien Vouillarmet5,
- Noël Peretti1,2,3,4,5,
- Rémi Rabas-Lhoret6,
- Martine Laville1,2,3,4,5,
- Hubert Vidal1,2,3,4,5 and
- Jennifer Rieusset ()1,2,3,4,5
- 1 INSERM, U-870, IFR62, Faculté de Médecine Lyon Sud, F-69600 Oullins, France
- 2 INRA, UMR1235, F-69600 Oullins, France
- 3 INSA-Lyon, RMND, F-69621 Villeurbanne, France
- 4 Université Lyon 1, F-69622 Lyon, France
- 5 Hospices Civils de Lyon, Service de Nutrition et Diabétologie, F-69008 Lyon, France
- 6 Montreal diabetes research center, Montreal university
Objectives. A strong association between genetic variants and obesity was found for the fat mass and obesity associated (FTO) gene. However, few details are known concerning the expression and function of FTO in skeletal muscle of patients with metabolic diseases.
Research Design and Methods. We investigated basal FTO expression in skeletal muscle from obese non diabetic subjects and type 1 and type 2 diabetic patients, compared to age-matched control subjects, and its regulation in vivo by insulin, glucose or rosiglitazone. The function of FTO was further studied in myotubes by over-expression experiments.
Results. We found a significant increase of FTO mRNA and protein levels in muscle from type 2 diabetic patients, whereas its expression was unchanged in obese or type 1 diabetic patients. Moreover, insulin or glucose infusion during specific clamps did not regulate FTO expression in skeletal muscle from control or type 2 diabetic patients. Interestingly, rosiglitazone treatment improved insulin sensitivity and reduced FTO expression in muscle from type 2 diabetic patients. In myotubes, adenoviral FTO over-expression increased basal PKB phosphorylation, enhanced lipogenesis and oxidative stress, and reduced mitochondrial oxidative function, a cluster of metabolic defects associated with type 2 diabetes.
Conclusions. This study demonstrates increased FTO expression in skeletal muscle from type 2 diabetic patients, which can be normalized by thiazolidinedione treatment. Furthermore, in vitro data support a potential implication of FTO in oxidative metabolism, lipogenesis and oxidative stress in muscle, suggesting that it could be involved in the muscle defects that characterize type 2 diabetes.
- Received February 25, 2010.
- Accepted October 4, 2010.
- Copyright © American Diabetes Association