Opposite Effects of Quercetin, Luteolin, and Epigallocatechin Gallate on Insulin Sensitivity Under Normal and Inflammatory Conditions in Mice.
ABSTRACT Flavonoids are polyphenolic compounds ubiquitous in plants. Quercetin, luteolin, and epigallocatechin gallate (EGCG) are flavonoids with a number of biochemical and cellular actions relevant to glucose homeostasis, but their regulation of insulin action is still uncertain. This study aims to evaluate the regulation of insulin action by quercetin, luteolin, and EGCG under normal and inflammatory conditions in mice. Oral administration of quercetin, luteolin, and EGCG impaired glucose tolerance and blunted the effect of insulin to low blood glucose. Luteolin and EGCG, but not quercetin, inhibited glucose load-induced insulin receptor substrate-1(IRS-1) tyrosine and Akt phosphorylation in adipose tissue. Meanwhile, insulin-stimulated glucose uptake was also inhibited by these flavonoids. We induced insulin resistance in mice by treatment with activated macrophages-derived conditioned medium (Mac-CM) and observed that quercetin, luteolin, and EGCG reversed glucose intolerance with improving insulin sensitivity. Quercetin, luteolin, and EGCG inhibited inflammation-evoked IKKβ activation and IRS-1 serine phosphorylation in adipose tissue, and thereby effectively restored glucose load-stimulated IRS-1 tyrosine and Akt phosphorylation, leading to an increase in insulin-mediated glucose uptake in adipocytes. The aforementioned results showed opposite effects of quercetin, luteolin, and EGCG on insulin sensitivity in mice. The different modulation of IRS-1 function by phosphorylating modification under normal and inflammatory conditions should be a key controlling for their action in regulation of insulin sensitivity.
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ABSTRACT: Mast cells play important roles in diet-induced obesity and diabetes, and some synthetic mast cell stabilizers can improve related metabolic disturbances in mice. Luteolin (LU) is a potent natural mast cell stabilizer. However, a direct correlation between LU and these common metabolic diseases is not established. Male C57BL/6 mice were fed low-fat diet, high-fat diet (HFD), HFD with 0.002 and 0.01% LU for 12 wk, respectively. Dietary LU suppressed HFD-induced body weight gain, fat deposition, and adipocyte hypertrophy. Meanwhile, glucose intolerance and insulin sensitivity was also improved. Interestingly, dietary LU ameliorated angiogenesis and associated cell apoptosis and cathepsin activity in epididymis adipose tissues, which is a critical mechanism that mast cells are involved in diet-induced obesity and diabetes. Further, we showed dietary LU reduced mast cell and macrophage infiltrations and inflammatory cytokine levels in epididymis adipose tissues. Finally, LU inhibited mast cell-derived IL-6 expression, which is a key cytokine that contributes to mast cell-associated metabolic derangements, and protein kinase C activator phorbol myristoyl acetate reversed the inhibitory effects. As a natural flavonoid, low-dose diet supplement of LU ameliorates diet-induced obesity and insulin resistance in mice, suggesting a new therapeutic and interventional approach for these diseases.Molecular Nutrition & Food Research 02/2014; · 4.31 Impact Factor
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ABSTRACT: Cyclocarya paliurus Batal., a Chinese native plant, is the sole species in its genus and its leaves have been widely used as a remedy for diabetes in traditional folk medicine. The study was undertaken to evaluate the effects of Cyclocarya paliurus leaves extracts (CPE) on adipokine expression and insulin sensitivity in mice. Mice were stimulated with conditioned medium (prepared from activated macrophages, Mac-CM) to induce adipose dysfunction and insulin resistance. Then mice were treated with CPE (100, 200 and 500mg/kg, ig.) or metformin (200mg/kg, ig.), followed by glucose and insulin intolerance, adipokine expression, phosphorylation of insulin receptor substrate (IRS-1) and glucose consumption measurement. CPE, as well as metformin effectively promoted glucose disposal in oral glucose tolerance test in normal mice. Mac-CM challenge induced glucose and insulin intolerance, but CPE reversed these alternations with increased glycogen content in muscle and liver, well demonstrating its beneficial effects on glucose homeostasis. RT-qPCR analysis showed that CPE inhibited TNF-a, IL-6, MCP-1 and resistin overexpression and effectively enhanced adiponectin expression in adipose tissue when mice were exposed to Mac-CM stimulation. Inflammation impaired insulin signaling in muscle, whereas CPE inhibited inflammation-induced serine phosphorylation of IRS-1 and effectively restored the phosphorylation of both IRS-1 at tyrosine residues and downstream Akt phosphorylation in response to insulin. Moreover, independently of insulin, CPE promoted glucose consumption in adipocytes under normal and inflammatory conditions. Above-mentioned results demonstrated that CPE beneficially regulated adipokines expression and ameliorated insulin resistance through inhibition of inflammation in mice.Journal of ethnopharmacology 02/2014; · 2.32 Impact Factor
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ABSTRACT: Quercetin is the most abundant dietary flavonol with beneficial regulation of glucose homeostasis, but its regulation of insulin action remains uncertain. This study aims to investigate the effects of quercetin on insulin-mediated glucose transporter 4 (GLUT4) translocation under basal and inflammatory conditions as well as the molecular mechanisms in adipocytes. The effects of quercetin on insulin-mediated GLUT4 translocation in 3T3-L1 cells under basal and insulin resistant conditions were investigated. Meanwhile, we investigated the effect of quercetin on AMP-activated protein kinase (AMPK) activation implicated in regulation of insulin action. Quercetin inhibited insulin-mediated GLUT4 translocation by inhibiting AS160 phosphorylation. Differently, when inflammatory challenge impaired insulin action in 3T3-L1 cells, quercetin inhibited IκB kinase β (IKKβ) phosphorylation and facilitated insulin signaling, leading to the restoration of insulin-mediated AS160 phosphorylation and downstream GLUT4 translocation. AMPK inhibitor Compound C or knockdown of AMPKα by small interfering RNA (siRNA) abolished both actions of quercetin. Results from mice adipose tissue (AT) further confirmed its positive regulation of AMPK phosphorylation and opposite effects on AS160 phosphorylation in vivo. Quercetin demonstrated divergent effects on insulin-mediated GLUT4 translocation in adipocytes under basal and insulin resistant conditions, which were related to its regulation of AMPK activity.Molecular Nutrition & Food Research 12/2013; · 4.31 Impact Factor