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. 2017 Feb;31(2):701-710.
doi: 10.1096/fj.201600832R. Epub 2016 Nov 3.

IL-10 Prevents Aging-Associated Inflammation and Insulin Resistance in Skeletal Muscle

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Free PMC article

IL-10 Prevents Aging-Associated Inflammation and Insulin Resistance in Skeletal Muscle

Sezin Dagdeviren et al. FASEB J. .
Free PMC article

Abstract

Altered energy balance and insulin resistance are important characteristics of aging. Skeletal muscle is a major site of glucose disposal, and the role of aging-associated inflammation in skeletal muscle insulin resistance remains unclear. To investigate, we examined glucose metabolism in 18-mo-old transgenic mice with muscle-specific overexpression of IL-10 (MIL10) and in wild-type mice during hyperinsulinemic-euglycemic clamping. Despite similar fat mass and energy balance, MIL10 mice were protected from aging-associated insulin resistance with significant increases in glucose infusion rates, whole-body glucose turnover, and skeletal muscle glucose uptake (∼60%; P < 0.05), as compared to age-matched WT mice. This protective effect was associated with decreased muscle inflammation, but no changes in adipose tissue inflammation in aging MIL10 mice. These results demonstrate the importance of skeletal muscle inflammation in aging-mediated insulin resistance, and our findings further implicate a potential therapeutic role of anti-inflammatory cytokine in the treatment of aging-mediated insulin resistance.-Dagdeviren, S., Jung, D. Y., Friedline, R. H., Noh, H. L., Kim, J. H., Patel, P. R., Tsitsilianos, N., Inashima, K., Tran, D. A., Hu, X., Loubato, M. M., Craige, S. M., Kwon, J. Y., Lee, K. W., Kim, J. K. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle.

Keywords: cytokines; aging; glucose metabolism; interleukins; type 2 diabetes.

Figures

Figure 1.
Figure 1.
Body weight and composition of MIL-10 and WT mice between 4 and 18 mo of age (n = 10–12 per group). A) Body weight. B, C) Whole-body lean (B) and fat (C) masses measured with 1H-MRS. *P < 0.05 vs. WT mice.
Figure 2.
Figure 2.
Longitudinal assessment of energy balance using metabolic cages in aging MIL-10 and WT mice (n = 6 per group). Data are averaged from a 3-d continuous measurement in mice at 12, 14, 16, and 18 mo of age. A) Energy expenditure rate. B) Respiratory exchange ratio. C) Daily food intake (caloric intake normalized to body weight). D) Hourly physical activity. *P < 0.05 vs. WT mice. #P < 0.05 vs. physical activity in WT mice at 12 mo of age.
Figure 3.
Figure 3.
A 2-h hyperinsulinemic–euglycemic clamping to assess insulin action and glucose metabolism in awake MIL-10 and WT mice at 18 mo of age (n = 9–10 per group). A) Steady-state glucose infusion rates during clamping. B–D) Whole-body glucose turnover (B), glycogen synthesis (C), and glycolysis (D). *P < 0.05 vs. WT mice.
Figure 4.
Figure 4.
Insulin signaling and glucose/lipid metabolism in skeletal muscle of MIL-10 and WT mice at 18 mo of age (n = 7–10 per group). A) Insulin-stimulated glucose uptake in skeletal muscle (gastrocnemius). B) Intramuscular (quadriceps) triglyceride levels. C) Total Akt and insulin-stimulated Akt phosphorylation at Ser473 in skeletal muscle (gastrocnemius). D) H&E staining of gastrocnemius muscle. *P < 0.05 vs. WT mice.
Figure 5.
Figure 5.
Skeletal muscle mRNA and protein levels of inflammatory cytokines, macrophages, and chemokines in MIL-10 and WT mice (n = 3–8 per group). A) Muscle IL-10 mRNA levels in WT mice at 4 mo (young) and 18 mo (aging) of age. B) Muscle mRNA levels of IL-10, CD68, IL-6, and TNF-α in aging MIL-10 and WT mice at 18 mo of age. C) Muscle protein levels of IL-10, IFN-γ, IL-1β, and MCP-1 in aging MIL-10 and WT mice at 18 mo of age. *P < 0.05 vs. young WT mice or WT mice.
Figure 6.
Figure 6.
Glucose metabolism and inflammation in adipose tissue and heart of aging MIL-10 and WT mice at 18 mo of age. A) Insulin-stimulated glucose uptake in WAT (epididymal) (n = 9–10 per group). B) WAT (epididymal) mRNA levels of F4/80 and TNF-α (n = 4–9 per group). C) Insulin-stimulated glucose uptake in BAT (intrascapular) (n = 9–10/group). D) Insulin-stimulated glucose uptake in heart (n = 4–5 per group). *P < 0.05 vs. WT mice.
Figure 7.
Figure 7.
HGP and hepatic insulin action during hyperinsulinemic–euglycemic clamp in awake MIL-10 and WT mice at 18 mo of age (n = 9–10 per group). A) Basal HGP. B) Insulin-stimulated HGP during clamping. C) Hepatic insulin action expressed as insulin-mediated percentage of suppression of basal HGP. D) Intrahepatic triglyceride levels. *P < 0.05 vs. WT mice.

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