FTO is increased in muscle during type 2 diabetes, and its overexpression in myotubes alters insulin signaling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 1; pp. 258 - 68
• Main Authors: Bravard, Amélie, Lefai, Etienne, Fouilloux-Meugnier, Emmanuelle, Pesenti, Sandra, Disse, Emmanuel, Vouillarmet, Julien, Peretti, Noël, Rabasa-Lhoret, Rémi, Laville, Martine, Vidal, Hubert, Rieusset, Jennifer
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01.01.2011
• Subjects: Adenosine Triphosphate; Biopsy; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Food and Nutrition; Gene Expression Regulation; Genetic Vectors; Hemoglobin A, Glycosylated; Humans; Hypoglycemic Agents; Insulin; Life Sciences; Male; Middle Aged; Mitochondria, Muscle; Muscle Fibers, Skeletal; Muscle, Skeletal; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Proteins; Reactive Oxygen Species; RNA; Signal Transduction; Thiazolidinediones; CELLS; OXIDATIVE STRESS; VARIANTS; GENE-EXPRESSION; RESISTANCE; HUMANS; ADULT OBESITY; HUMAN SKELETAL-MUSCLE; FAT MASS; ADIPOSE-TISSUE
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db10-0281

OBJECTIVE: A strong association between genetic variants and obesity was found for the fat mass and obesity-associated gene (FTO). 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 nondiabetic subjects and type 1 and type 2 diabetic patients, compared with age-matched control subjects, and its regulation in vivo by insulin, glucose, or rosiglitazone. The function of FTO was further studied in myotubes by overexpression 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 overexpression increased basal protein kinase B 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.