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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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Related in: MedlinePlus

Effect of FTO overexpression on insulin signaling in HEK293 cells. HEK293 were transiently transfected with pcDNA3-FTO or empty pcDNA3 vector (control). Forty-eight h posttransfection, cells were depleted in serum for 3 h and stimulated with insulin (10−7 M, 10 min). A: Representative Western blots of FTO, pSer473PKB, pThr308PKB, and total PKB. B: Histogram illustrates the quantification and normalization of the phosphorylation of PKB in control and FTO-overexpressing cells. Values are means ± SEM (n = 3). *P < 0.001 versus control cells, #P < 0.001 FTO versus GFP. Ins, insulin.
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Figure 2: Effect of FTO overexpression on insulin signaling in HEK293 cells. HEK293 were transiently transfected with pcDNA3-FTO or empty pcDNA3 vector (control). Forty-eight h posttransfection, cells were depleted in serum for 3 h and stimulated with insulin (10−7 M, 10 min). A: Representative Western blots of FTO, pSer473PKB, pThr308PKB, and total PKB. B: Histogram illustrates the quantification and normalization of the phosphorylation of PKB in control and FTO-overexpressing cells. Values are means ± SEM (n = 3). *P < 0.001 versus control cells, #P < 0.001 FTO versus GFP. Ins, insulin.

Mentions: To determine whether the observed upregulation of FTO in muscle from type 2 diabetic patients could contribute to altered insulin action, we transiently overexpressed FTO in HEK293 cells and investigated the consequences on insulin signaling. A twofold increase of FTO protein was associated with a marked increase of basal protein kinase B (PKB) phosphorylation on both Ser473 and Thr308 residues (Fig. 2). Furthermore, the insulin-stimulated phosphorylation of PKB was inhibited in FTO overexpressing cells (Fig. 2).


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)

Effect of FTO overexpression on insulin signaling in HEK293 cells. HEK293 were transiently transfected with pcDNA3-FTO or empty pcDNA3 vector (control). Forty-eight h posttransfection, cells were depleted in serum for 3 h and stimulated with insulin (10−7 M, 10 min). A: Representative Western blots of FTO, pSer473PKB, pThr308PKB, and total PKB. B: Histogram illustrates the quantification and normalization of the phosphorylation of PKB in control and FTO-overexpressing cells. Values are means ± SEM (n = 3). *P < 0.001 versus control cells, #P < 0.001 FTO versus GFP. Ins, insulin.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 2: Effect of FTO overexpression on insulin signaling in HEK293 cells. HEK293 were transiently transfected with pcDNA3-FTO or empty pcDNA3 vector (control). Forty-eight h posttransfection, cells were depleted in serum for 3 h and stimulated with insulin (10−7 M, 10 min). A: Representative Western blots of FTO, pSer473PKB, pThr308PKB, and total PKB. B: Histogram illustrates the quantification and normalization of the phosphorylation of PKB in control and FTO-overexpressing cells. Values are means ± SEM (n = 3). *P < 0.001 versus control cells, #P < 0.001 FTO versus GFP. Ins, insulin.
Mentions: To determine whether the observed upregulation of FTO in muscle from type 2 diabetic patients could contribute to altered insulin action, we transiently overexpressed FTO in HEK293 cells and investigated the consequences on insulin signaling. A twofold increase of FTO protein was associated with a marked increase of basal protein kinase B (PKB) phosphorylation on both Ser473 and Thr308 residues (Fig. 2). Furthermore, the insulin-stimulated phosphorylation of PKB was inhibited in FTO overexpressing cells (Fig. 2).

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