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 - 268
• Main Authors: Bravard, Amélie, Lefai, Etienne, Meugnier, Emmanuelle, Pesenti, Sandra, Disse, Emmanuel, Vouillarmet, Julien, Peretti, Nöel, Rabasa-Lhoret, Rémi, Laville, Martine, Vidal, Hubert, Rieusset, Jennifer
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2011
• Subjects: Adenosine Triphosphate - metabolism; Age; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Biological and medical sciences; Biopsy; Blood Glucose - metabolism; Body fat; Cellular signal transduction; Cloning; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene expression; Gene Expression Regulation; Genetic aspects; Genetic Vectors; Glucose; Glycated Hemoglobin A - metabolism; Humans; Hypoglycemic Agents - therapeutic use; Insulin; Insulin - physiology; Insulin - therapeutic use; Kinases; Life Sciences; Male; Medical sciences; Metabolic disorders; Middle Aged; Mitochondria, Muscle - pathology; Mitochondrial diseases; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Musculoskeletal system; Obesity; Oligonucleotide Array Sequence Analysis; Oxidative stress; Oxidative Stress - physiology; Pathophysiology; Physiological aspects; Prevention; Proteins; Proteins - genetics; Proteins - metabolism; Reactive Oxygen Species - metabolism; Research design; Risk factors; RNA - genetics; RNA - isolation & purification; Signal Transduction; Thiazolidinediones - therapeutic use; Type 2 diabetes; Women; Canada; Endocrinopathy; Type 2 diabetes; Signal transduction; Pancreatic hormone; Mitochondria; Dysfunction; Gene overexpression; Metabolic diseases; Muscle; Myotube; Lipogenesis; Insulin
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db10-0281

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. 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. 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. 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.