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Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.

ABSTRACT: Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (M^IL10). After 16 weeks of a high-fat diet (HFD), M^IL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice. Muscle-specific overexpression of IL-10 in ob/ob mice (MCK-IL10^ob/ob) did not affect spontaneous obesity, but MCK-IL10^ob/ob mice showed increased glucose turnover compared to that in ob/ob mice. Last, mice with muscle-specific ablation of IL-10 receptor (M-IL10R^-/-) were generated to determine whether IL-10 signaling in skeletal muscle is involved in IL-10 effects on glucose metabolism. After an HFD, M-IL10R^-/- mice developed insulin resistance with reduced glucose metabolism compared to that in wild-type mice. Overall, these results demonstrate IL-10 effects to attenuate obesity-mediated inflammation and improve insulin sensitivity in skeletal muscle, and our findings implicate a potential therapeutic role of anti-inflammatory cytokines in treating insulin resistance and type 2 diabetes.

SUBMITTER: Dagdeviren S

PROVIDER: S-EPMC5108883 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.

Dagdeviren Sezin S Jung Dae Young DY Lee Eunjung E Friedline Randall H RH Noh Hye Lim HL Kim Jong Hun JH Patel Payal R PR Tsitsilianos Nicholas N Tsitsilianos Andrew V AV Tran Duy A DA Tsougranis George H GH Kearns Caitlyn C CC Uong Cecilia P CP Kwon Jung Yeon JY Muller Werner W Lee Ki Won KW Kim Jason K JK

Molecular and cellular biology 20161114 23

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (M<sup>IL10</sup>). After 16 weeks of a high-fat diet (HFD), M<sup>IL10</sup> mice became markedly obese but showed improved insulin action compared to that of wild-type mi ...[more]

PMID: 27644327

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Project description:The pro-inflammatory cytokine, Interleukin-6 (IL-6), has been proposed to be one of the mediators that link chronic inflammation to glucose intolerance and insulin resistance. Many studies have demonstrated the effects of IL-6 on insulin action in the skeletal muscle. However, few studies have investigated the effect of long-term treatment of IL-6, leading to glucose intolerance and insulin resistance. In the present study, we observed protective effects of alantolactone, a sesquiterpene lactone isolated from Inula helenium against glucose intolerance and insulin resistance induced by prolonged exposure of IL-6. Alantolactone has been reported to have anti-inflammatory and anti-cancer effects through IL-6-induced signal transducer and activator of transcription 3 (STAT3) signaling pathway. The relationship between IL-6 exposure and expression of toll-like receptor 4 (TLR4), involved in inflammation in the skeletal muscle, and the underlying mechanisms were investigated. We observed maximum dysregulation of glucose uptake after 40 ng/ml IL-6 induction for 24 h in L6 myotubes. Prolonged IL-6 exposure suppressed glucose uptake regulating alpha serine/threonine-protein kinase (AKT) phosphorylation; however, pretreatment with alantolactone activated AKT phosphorylation and improved glucose uptake. Alantolactone also attenuated IL-6-stimulated STAT3 phosphorylation, followed by an increase in expression of negative regulator suppressor of cytokine signaling 3 (SOCS3). Furthermore, IL-6-induced expression of pathogen recognition receptor, TLR4, was also suppressed by alantolactone pretreatment. Post-silencing of STAT3 using siRNA approach, IL-6-stimulated siRNA-STAT3 improved glucose uptake and suppressed TLR4 gene expression. Taken together, we propose that, as a STAT3 inhibitor, alantolactone, improves glucose regulation in the skeletal muscle by inhibiting IL-6-induced STAT3-SOCS3 signaling followed by inhibition of the TLR4 gene expression. Therefore, alantolactone can be a promising candidate for the treatment of inflammation-associated glucose intolerance and insulin resistance.

Project description:ObjectivePhysical exercise training is associated with increased glucose uptake in skeletal muscle and improved glycemic control. HDAC5, a class IIa histone deacetylase, has been shown to regulate transcription of the insulin-responsive glucose transporter GLUT4 in cultured muscle cells. In this study, we analyzed the contribution of HDAC5 to the transcriptional network in muscle and the beneficial effect of muscle contraction and regular exercise on glucose metabolism.MethodsHDAC5 knockout mice (KO) and wild-type (WT) littermates were trained for 8 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. Hdac5-deficient skeletal muscle and cultured Hdac5-knockdown (KD) C2C12 myotubes were utilized for studies of gene expression and glucose metabolism. Chromatin immunoprecipitation (ChIP) studies were conducted to analyze Il6 promoter activity using H3K9ac and HDAC5 antibodies.ResultsGlobal transcriptome analysis of Hdac5 KO gastrocnemius muscle demonstrated activation of the IL-6 signaling pathway. Accordingly, knockdown of Hdac5 in C2C12 myotubes led to higher expression and secretion of IL-6 with enhanced insulin-stimulated activation of AKT that was reversed by Il6 knockdown. Moreover, Hdac5-deficient myotubes exhibited enhanced glucose uptake, glycogen synthesis, and elevated expression levels of the glucose transporter GLUT4. Transcription of Il6 was further enhanced by electrical pulse stimulation in Hdac5-deficient C2C12 myotubes. ChIP identified a ∼1 kb fragment of the Il6 promoter that interacts with HDAC5 and demonstrated increased activation-associated histone marker AcH3K9 in Hdac5-deficient muscle cells. Exercise intervention of HDAC5 KO mice resulted in improved systemic glucose tolerance as compared to WT controls.ConclusionsWe identified HDAC5 as a negative epigenetic regulator of IL-6 synthesis and release in skeletal muscle. HDAC5 may exert beneficial effects through two different mechanisms, transcriptional control of genes required for glucose disposal and utilization, and HDAC5-dependent IL-6 signaling cross-talk to improve glucose uptake in muscle in response to exercise.

Project description:ContextObesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity.ObjectivesWe compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development.Methods30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression.ResultsSystemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR.ConclusionOur results show that systemic IR occurs without any change in systemic and tissues inflammation. We identified a muscle defect in insulin response as an early mechanism of IR development in grade I obese post-menopausal women.

Dataset Information

Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.

Publications

Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.

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