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IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle
Dagdeviren, Sezin,Jung, Dae Young,Friedline, Randall H.,Noh, Hye Lim,Kim, Jong Hun,Patel, Payal R.,Tsitsilianos, Nicholas,Inashima, Kunikazu,Tran, Duy A.,Hu, Xiaodi,Loubato, Marilia M.,Craige, Siobhan The Federation of American Societies for Experimen 2017 The FASEB Journal Vol.31 No.2
<P>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 (M-IL10) and in wild-type mice during hyperinsulinemic-euglycemic clamping. Despite similar fat mass and energy balance, M-IL10 mice were protected from aging-associated insulin resistance with significant increases in glucose infusion rates, whole-body glucose turnover, and skeletal muscle glucose uptake (similar to 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 M-IL10 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.</P>
Kim, Jong Hun,Lee, Eunjung,Friedline, Randall H.,Suk, Sujin,Jung, Dae Young,Dagdeviren, Sezin,Hu, Xiaodi,Inashima, Kunikazu,Noh, Hye Lim,Kwon, Jung Yeon,Nambu, Aya,Huh, Jun R.,Han, Myoung Sook,Davis, Federation of American Society for Experimental Bi 2018 The FASEB Journal Vol.32 No.4
<P>Obesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage-selective ablation of GRP78 (Lyz-GRP78(-/-)) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet. GRP78-deficient macrophages demonstrated adapted UPR with up-regulation of activating transcription factor (ATF)-4 and M2-polarization markers. Diet-induced adipose tissue inflammation was reduced, and bone marrow-derived macrophages from Lyz-GRP78(-/-) mice demonstrated a selective increase in IL-6 expression. Serum IL-13 levels were elevated by >4-fold in Lyz-GRP78(-/-) mice, and IL-6 stimulated the myocyte expression of IL-13 and IL-13 receptor. Lastly, recombinant IL-13 acutely increased glucose metabolism in Lyz-GRP78(-/-) mice. Taken together, our data indicate that GRP78 deficiency activates UPR by increasing ATF-4, and promotes M2-polarization of macrophages with a selective increase in IL-6 secretion. Macrophage-derived IL-6 stimulates the myocyte expression of IL-13 and regulates muscle glucose metabolism in a paracrine manner. Thus, our findings identify a novel crosstalk between macrophages and skeletal muscle in the modulation of obesity-mediated insulin resistance.</P>
Friedline, Randall H.,Ko, Hwi Jin,Jung, Dae Young,Lee, Yongjin,Bortell, Rita,Dagdeviren, Sezin,Patel, Payal R.,Hu, Xiaodi,Inashima, Kunikazu,Kearns, Caitlyn,Tsitsilianos, Nicholas,Shafiq, Umber,Shultz The Federation of American Societies for Experimen 2016 The FASEB Journal Vol.30 No.3
<P>Obesity is characterized by a dysregulated immune system, which may causally associate with insulin resistance and type 2 diabetes. Despite widespread use of nonobese diabetic (NOD) mice, NOD with severe combined immunodeficiency (scid) mutation (SCID) mice, and SCID bearing a null mutation in the IL-2 common chain receptor (NSG) mice as animal models of human diseases including type 1 diabetes, the underlying metabolic effects of a genetically altered immune system are poorly understood. For this, we performed a comprehensive metabolic characterization of these mice fed chow or after 6 wk of a high-fat diet. We found that NOD mice had similar to 50% less fat mass and were 2-fold more insulin sensitive, as measured by hyperinsulinemic-euglycemic clamp, than C57BL/6 wild-type mice. SCID mice were also more insulin sensitive with increased muscle glucose metabolism and resistant to diet-induced obesity due to increased energy expenditure (similar to 10%) and physical activity (similar to 40%) as measured by metabolic cages. NSG mice were completely protected from diet-induced obesity and insulin resistance with significant increases in glucose metabolism in peripheral organs. Our findings demonstrate an important role of genetic background, lymphocytes, and cytokine signaling in diet-induced obesity and insulin resistance.</P>