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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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Regulation of FTO expression in human skeletal muscle. A: Basal FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control, obese, type 2 diabetic patients, and type 1 diabetic subjects. Values are means ± SEM (n = 5–10). *P < 0.05 versus age-matched control subjects. The mRNA level of the reference gene HPRT did not differ among groups (3.9 ± 0.5, 2.9 ± 0.1, 3.8 ± 0.5, 3.3 ± 0.3, and 4.2 ± 0.5 amo/μg total RNA, in control 50, obese, type 2 diabetic patients [T2DM], control 25, and type 1 diabetic patients [T1DM], respectively, not significant [NS]). B: Representative Western blot illustrating FTO protein levels in skeletal muscle of age-matched control, obese, and type 2 diabetic patients. Data of the histogram are means ± SEM (n = 3). *P < 0.05 versus age-matched control subjects. C and D: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control and type 2 diabetic patients, before and after a 3-h euglycemic hyperinsulinemic clamp (C) or a 3-h hyperglycemic euinsulinemic clamp (D). Values are means ± SEM (n = 6). E: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of type 2 diabetic patients, before and after a 12-week rosiglitazone treatment. Values are means ± SEM (n = 6). *P < 0.05 versus before treatment. The mRNA level of the reference gene HPRT did not differ before and after rosiglitazone treatment (5 ± 0.6 and 6.6 ± 0.5 amo/μg total RNA, respectively, NS). a.u., arbitrary units.
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Figure 1: Regulation of FTO expression in human skeletal muscle. A: Basal FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control, obese, type 2 diabetic patients, and type 1 diabetic subjects. Values are means ± SEM (n = 5–10). *P < 0.05 versus age-matched control subjects. The mRNA level of the reference gene HPRT did not differ among groups (3.9 ± 0.5, 2.9 ± 0.1, 3.8 ± 0.5, 3.3 ± 0.3, and 4.2 ± 0.5 amo/μg total RNA, in control 50, obese, type 2 diabetic patients [T2DM], control 25, and type 1 diabetic patients [T1DM], respectively, not significant [NS]). B: Representative Western blot illustrating FTO protein levels in skeletal muscle of age-matched control, obese, and type 2 diabetic patients. Data of the histogram are means ± SEM (n = 3). *P < 0.05 versus age-matched control subjects. C and D: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control and type 2 diabetic patients, before and after a 3-h euglycemic hyperinsulinemic clamp (C) or a 3-h hyperglycemic euinsulinemic clamp (D). Values are means ± SEM (n = 6). E: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of type 2 diabetic patients, before and after a 12-week rosiglitazone treatment. Values are means ± SEM (n = 6). *P < 0.05 versus before treatment. The mRNA level of the reference gene HPRT did not differ before and after rosiglitazone treatment (5 ± 0.6 and 6.6 ± 0.5 amo/μg total RNA, respectively, NS). a.u., arbitrary units.

Mentions: Type 2 diabetic patients had significantly higher skeletal muscle FTO mRNA levels compared either to age-matched lean control subjects or to obese nondiabetic subjects (Fig. 1A). However, there was no difference between lean control subjects and obese nondiabetic subjects (Fig. 1A). It should be noted that the FTO mRNA levels in skeletal muscle were positively correlated with A1C (r = 0.62, P = 0.04) and glycemia (r = 0.5, P = 0.02) and a tendency was observed with the basal rate of lipid oxidation (r = −0.48, P = 0.06). However, we did not observe correlation of FTO mRNA levels with glucose disposal during the clamp (r = 0.22, P = 0.43). In addition, increased FTO expression was also demonstrated at the protein level in muscle from type 2 diabetic patients (Fig. 1B). Interestingly, there was no difference in FTO mRNA levels between type 1 diabetic subjects and age-matched control subjects (Fig. 1A), suggesting that the upregulation of FTO expression observed in type 2 diabetic subjects was not related to chronic hyperglycemia (Fig. 1A).


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)

Regulation of FTO expression in human skeletal muscle. A: Basal FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control, obese, type 2 diabetic patients, and type 1 diabetic subjects. Values are means ± SEM (n = 5–10). *P < 0.05 versus age-matched control subjects. The mRNA level of the reference gene HPRT did not differ among groups (3.9 ± 0.5, 2.9 ± 0.1, 3.8 ± 0.5, 3.3 ± 0.3, and 4.2 ± 0.5 amo/μg total RNA, in control 50, obese, type 2 diabetic patients [T2DM], control 25, and type 1 diabetic patients [T1DM], respectively, not significant [NS]). B: Representative Western blot illustrating FTO protein levels in skeletal muscle of age-matched control, obese, and type 2 diabetic patients. Data of the histogram are means ± SEM (n = 3). *P < 0.05 versus age-matched control subjects. C and D: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control and type 2 diabetic patients, before and after a 3-h euglycemic hyperinsulinemic clamp (C) or a 3-h hyperglycemic euinsulinemic clamp (D). Values are means ± SEM (n = 6). E: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of type 2 diabetic patients, before and after a 12-week rosiglitazone treatment. Values are means ± SEM (n = 6). *P < 0.05 versus before treatment. The mRNA level of the reference gene HPRT did not differ before and after rosiglitazone treatment (5 ± 0.6 and 6.6 ± 0.5 amo/μg total RNA, respectively, NS). a.u., arbitrary units.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: Regulation of FTO expression in human skeletal muscle. A: Basal FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control, obese, type 2 diabetic patients, and type 1 diabetic subjects. Values are means ± SEM (n = 5–10). *P < 0.05 versus age-matched control subjects. The mRNA level of the reference gene HPRT did not differ among groups (3.9 ± 0.5, 2.9 ± 0.1, 3.8 ± 0.5, 3.3 ± 0.3, and 4.2 ± 0.5 amo/μg total RNA, in control 50, obese, type 2 diabetic patients [T2DM], control 25, and type 1 diabetic patients [T1DM], respectively, not significant [NS]). B: Representative Western blot illustrating FTO protein levels in skeletal muscle of age-matched control, obese, and type 2 diabetic patients. Data of the histogram are means ± SEM (n = 3). *P < 0.05 versus age-matched control subjects. C and D: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of age-matched control and type 2 diabetic patients, before and after a 3-h euglycemic hyperinsulinemic clamp (C) or a 3-h hyperglycemic euinsulinemic clamp (D). Values are means ± SEM (n = 6). E: FTO mRNA levels were measured by real-time RT-PCR in skeletal muscle of type 2 diabetic patients, before and after a 12-week rosiglitazone treatment. Values are means ± SEM (n = 6). *P < 0.05 versus before treatment. The mRNA level of the reference gene HPRT did not differ before and after rosiglitazone treatment (5 ± 0.6 and 6.6 ± 0.5 amo/μg total RNA, respectively, NS). a.u., arbitrary units.
Mentions: Type 2 diabetic patients had significantly higher skeletal muscle FTO mRNA levels compared either to age-matched lean control subjects or to obese nondiabetic subjects (Fig. 1A). However, there was no difference between lean control subjects and obese nondiabetic subjects (Fig. 1A). It should be noted that the FTO mRNA levels in skeletal muscle were positively correlated with A1C (r = 0.62, P = 0.04) and glycemia (r = 0.5, P = 0.02) and a tendency was observed with the basal rate of lipid oxidation (r = −0.48, P = 0.06). However, we did not observe correlation of FTO mRNA levels with glucose disposal during the clamp (r = 0.22, P = 0.43). In addition, increased FTO expression was also demonstrated at the protein level in muscle from type 2 diabetic patients (Fig. 1B). Interestingly, there was no difference in FTO mRNA levels between type 1 diabetic subjects and age-matched control subjects (Fig. 1A), suggesting that the upregulation of FTO expression observed in type 2 diabetic subjects was not related to chronic hyperglycemia (Fig. 1A).

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