Purpose Intramyocellular triglyceride (IMTG) content is known to be increased in states of insulin resistance and type 2 diabetes (T2DM), but the mechanism remains unclear. SREBP-1 is a transcription factor that regulates lipid synthesis, and because it is up-regulated by insulin, could mechanistically link insulin resistance and compensatory hyperinsulinemia with increased IMTG. Furthermore, medications used to treat T2DM or dyslipidemia may affect SREBP-1 and subsequently IMTG.
Methods In this study, we examined the effects of fenofibrate (FF) and rosiglitazone (Rosi) on SREBP-1 expression in skeletal muscle of 24 Zucker diabetic fatty rats (ZDF, an animal model of T2DM) and 6 age-matched controls. ZDF animals were treated with chow mixed with FF, Rosi, both drugs combined, or standard chow for approximately 25 weeks (6 in each group). Skeletal muscle (gastrocnemius) SREBP-1 expression was assessed by either RT-PCR (mRNA levels) or Western blotting (protein levels).
Results Control animals weighed significantly less than untreated ZDF (394 ± 3g vs 431 ± 5 g, p = .01). Weights were higher after treatment with Rosi (796 ± 5 g, p < .001) or Rosi/FF (642 ± 3.7g, p = .01) and lower with FF (364 ± 8 g, p = .03) than in untreated ZDF. Treatment with Rosi and Rosi/FF significantly improved glycemia (168 ± 6 mg/dL, p < .01; 223 ± 14 mg/dL, p = .02, respectively) vs untreated (481 ± 15 mg/dL, p < .01) or FF-treated rats (421 ± 13 mg/dL, p < .02). SREBP-1c mRNA was significantly higher in untreated ZDF than controls (5.7 ± 2.7 vs 1.3 ± 0.2, p = .004). Treatment of ZDF with FF significantly reduced SREBP-1 mRNA levels from 5.7 ± 2.7 to 3.0 ± 1.9 (p = .01) and SREBP-1 protein by 50% (p = .002). In contrast, treatment with Rosi failed to decrease SREBP-1 protein or mRNA levels, while Rosi/FF showed a nonsignificant trend toward lowering SREBP-1 mRNA and SREBP-1 protein.
Conclusion Skeletal muscle SREBP-1 is higher in the hyperglycemic ZDF and is reduced by treatment with FF. Rosi, despite improvement in glycemia, failed to affect SREBP-1 expression.
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