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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.

Bravard A, Lefai E, Meugnier E, Pesenti S, Disse E, Vouillarmet J, Peretti N, Rabasa-Lhoret R, Laville M, Vidal H, Rieusset J - Diabetes (2010)

Bottom Line: A strong association between genetic variants and obesity was found for the fat mass and obesity-associated gene (FTO).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.

View Article: PubMed Central - PubMed

Affiliation: INSERM, IFR, Oullins, France.

ABSTRACT

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.

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Reduced OXPHOS and antioxidant genes and increased oxidative stress in skeletal muscle of type 2 diabetic patients. A: mRNA levels of ATP5B, UQCR, SOD2, and PGC1α were measured by real-time RT-PCR in skeletal muscle of control and type 2 diabetic patients. Data represent means ± SEM (n = 10). *P < 0.05. B: Immunoblot showing total protein carbonylation in skeletal muscle of control and type 2 diabetic patients. Histogram represents means ± SEM (n = 4).*P < 0.05. ATP5B, ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide; UQCR, ubiquinol-cytochrome c reductase; SOD2, superoxide dismutase 2; a.u., arbitrary units; T2DM, type 2 diabetes.
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Figure 6: Reduced OXPHOS and antioxidant genes and increased oxidative stress in skeletal muscle of type 2 diabetic patients. A: mRNA levels of ATP5B, UQCR, SOD2, and PGC1α were measured by real-time RT-PCR in skeletal muscle of control and type 2 diabetic patients. Data represent means ± SEM (n = 10). *P < 0.05. B: Immunoblot showing total protein carbonylation in skeletal muscle of control and type 2 diabetic patients. Histogram represents means ± SEM (n = 4).*P < 0.05. ATP5B, ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide; UQCR, ubiquinol-cytochrome c reductase; SOD2, superoxide dismutase 2; a.u., arbitrary units; T2DM, type 2 diabetes.

Mentions: To confirm in vivo the relevance of our in vitro observations, we measured some FTO-regulated mitochondria genes in skeletal muscle of control and type 2 diabetic patients. We measured the expression of three FTO-regulated genes, selected in Table 2 on their implication on oxidative metabolism (ATP5B, UQCR) and oxidative stress (SOD2). As observed in vitro, we found a significant reduction of ATP5B and SOD2 in muscle of type 2 diabetic patients compared with control subjects (Fig. 6A), whereas a tendency to reduction was observed for UQCR (P = 0.06). In addition, PGC1α expression is significantly reduced in muscle of type 2 diabetic patients (Fig. 6A). Lastly, protein carbonylation is induced in muscle of type 2 diabetic patients (Fig. 6B), indicating an increase of oxidative stress.


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.

Bravard A, Lefai E, Meugnier E, Pesenti S, Disse E, Vouillarmet J, Peretti N, Rabasa-Lhoret R, Laville M, Vidal H, Rieusset J - Diabetes (2010)

Reduced OXPHOS and antioxidant genes and increased oxidative stress in skeletal muscle of type 2 diabetic patients. A: mRNA levels of ATP5B, UQCR, SOD2, and PGC1α were measured by real-time RT-PCR in skeletal muscle of control and type 2 diabetic patients. Data represent means ± SEM (n = 10). *P < 0.05. B: Immunoblot showing total protein carbonylation in skeletal muscle of control and type 2 diabetic patients. Histogram represents means ± SEM (n = 4).*P < 0.05. ATP5B, ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide; UQCR, ubiquinol-cytochrome c reductase; SOD2, superoxide dismutase 2; a.u., arbitrary units; T2DM, type 2 diabetes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3012179&req=5

Figure 6: Reduced OXPHOS and antioxidant genes and increased oxidative stress in skeletal muscle of type 2 diabetic patients. A: mRNA levels of ATP5B, UQCR, SOD2, and PGC1α were measured by real-time RT-PCR in skeletal muscle of control and type 2 diabetic patients. Data represent means ± SEM (n = 10). *P < 0.05. B: Immunoblot showing total protein carbonylation in skeletal muscle of control and type 2 diabetic patients. Histogram represents means ± SEM (n = 4).*P < 0.05. ATP5B, ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide; UQCR, ubiquinol-cytochrome c reductase; SOD2, superoxide dismutase 2; a.u., arbitrary units; T2DM, type 2 diabetes.
Mentions: To confirm in vivo the relevance of our in vitro observations, we measured some FTO-regulated mitochondria genes in skeletal muscle of control and type 2 diabetic patients. We measured the expression of three FTO-regulated genes, selected in Table 2 on their implication on oxidative metabolism (ATP5B, UQCR) and oxidative stress (SOD2). As observed in vitro, we found a significant reduction of ATP5B and SOD2 in muscle of type 2 diabetic patients compared with control subjects (Fig. 6A), whereas a tendency to reduction was observed for UQCR (P = 0.06). In addition, PGC1α expression is significantly reduced in muscle of type 2 diabetic patients (Fig. 6A). Lastly, protein carbonylation is induced in muscle of type 2 diabetic patients (Fig. 6B), indicating an increase of oxidative stress.

Bottom Line: A strong association between genetic variants and obesity was found for the fat mass and obesity-associated gene (FTO).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.

View Article: PubMed Central - PubMed

Affiliation: INSERM, IFR, Oullins, France.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus