Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes

Abstract

Quercetin is a potent anti-inflammatory flavonoid, but its capacity to modulate insulin sensitivity in obese insulin resistant conditions is unknown. This study investigated the effect of quercetin treatment upon insulin sensitivity of ob/ob mice and its potential molecular mechanisms. Obese ob/ob mice were treated with quercetin for 10 weeks, and L6 myotubes were treated with either palmitate or tumor necrosis factor-α (TNFα) plus quercetin. Cells and muscles were processed for analysis of glucose transporter 4 (GLUT4), TNFα and inducible nitric oxide synthase (iNOS) expression, and c-Jun N-terminal kinase (JNK) and inhibitor of nuclear factor-κB (NF-κB) kinase (IκK) phosphorylation. Myotubes were assayed for glucose uptake and NF-κB translocation. Chromatin immunoprecipitation assessed NF-κB binding to GLUT4 promoter. Quercetin treatment improved whole body insulin sensitivity by increasing GLUT4 expression and decreasing JNK phosphorylation, and TNFα and iNOS expression in skeletal muscle. Quercetin suppressed palmitate-induced upregulation of TNFα and iNOS and restored normal levels of GLUT4 in myotubes. In parallel, quercetin suppressed TNFα-induced reduction of glucose uptake in myotubes. Nuclear accumulation of NF-κB in myotubes and binding of NF-κB to GLUT4 promoter in muscles of ob/ob mice were also reduced by quercetin. We demonstrated that quercetin decreased the inflammatory status in skeletal muscle of obese mice and in L6 myotubes. This effect was followed by increased muscle GLUT4, with parallel improvement of insulin sensitivity. These results point out quercetin as a putative strategy to manage inflammatory-related insulin resistance.

Quercetin But Not Quercitrin Ameliorates Tumor Necrosis Factor-Alpha-Induced Insulin Resistance in C2C12 Skeletal Muscle Cells

“…Also, previous studies have demonstrated that quercetin could increase GLUT4 in both ob/ob mice and skeletal muscle myotubes. 28,29) And, we noticed that some study found that quercetin inhibited glucose uptake in normal adipocytes 30,31) or acutely impaired glucose metabolism in hamsters, 32) however, as quercetin may be of little value in normalglycemic animals 33) and the ways of glucose utilization remains some difference between skeletal muscle and adipose tissue, the weight of such negative results from nondiabetic animal or cells seems weakened. In addition, we did not find that the glycoside quercitrin enhanced glucose uptake in these cells (chemical structures shown in Fig.…”

“…Importantly, we found that quercetin mitigated TNF-α induced insulin resistance in C2C12 myotubes, however, the effect is moderate and weaker than the result from Anhe et al where quercetin have a more marked enhancement effect toward the impaired insulin stimulated glucose uptake by TNF-α in L6 myotubes. 29) We suppose that C2C12 may be less sensitive than L6 myotubes when stimulated by quercetin under insulin resistance. TNF-α is a proinflammatory cytokine that triggers several signaling cascades, including critical insulin action inhibitors, 8,34) and the precise molecular signals underlying TNF-α induced metabolic dysregulation remain obscure.…”

Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation

“…The authors of those studies which found positive effects of quercetin on glycemic control proposed several mechanisms to explain the beneficial effect of this polyphenol: (a) the anti-oxidative protective action on the pancreatic islets (Coskun et al 2005;Babujanarthanam et al 2010;Jeong et al 2012), (b) the increase in adiponectin circulating concentration (Wein et al 2010), (c) the inhibition of small intestine glucosidase activity , (d) the reduction in the intestinal glucose absorption mediated by GLUT2 (Kwon et al 2007), (e) the increase in glucokinase activity (Vessal et al 2003) and (f) the increase in GLUT4 transporters in skeletal muscle (Jung et al 2011;Shen et al 2012;Anhê et al 2012).…”

Pharmacological Applications of Quercetin and its Derivatives: A Short Review

“…However, in vivo study in mice has been reported to show a reduction in expression of inflammatory genes by using quercetin enriched diet [37]. An improvement in insulin sensitivity has been reported by intraperitoneal administration of quercetin in mice, subsequently a reduction in inflammation was reported which is attributed to the insulin resistance [38]. However, during in vivo and ex vivo studies performed in healthy human volunteers administered with quercetin reported no effect on inflammatory agents present in human blood [39].…”

“…Antioxidant activity [4], [5], [6], [7], [8] [16], [17], [18], [19], [20], [21], [22] Anticancer activity [2], [23], [24], [25], [26] Cardiovascular protection [4], [27], [28], [29], [30] Antimicrobial activity [31], [32], [33] Anti-inflammatory activity [34], [35], [36], [37], [38], [39] Hepatoprotective activity [40], [41], [42] …”