peoniflorin and Insulin-Resistance

Polycystic ovary syndrome (PCOS) is a complex heterogeneous disorder characterized by androgen excess and ovulatory dysfunction; it is now known to be closely linked to metabolic syndrome. Recent research suggests that insulin resistance plays an important role in the pathogenesis of PCOS which may lead to the excessive production of androgens by ovarian theca cells. Currently there is no single drug that can treat both the reproductive and metabolic complications of the disorder. Existing pharmaceutical agents such as hormonal therapies have been associated with side effects and are not appropriate for PCOS women with infertility. Additionally, insulin sensitizing agents useful for treating the metabolic abnormalities in PCOS have limited efficacy for treating reproductive aspects of the disorder. Chinese herbal medicines have a long history of treating gynaecological problems and infertility and therefore may be a novel approach to the treatment of PCOS. Current research demonstrates that the compounds isolated from herbs have shown beneficial effects for PCOS and when combined in an herbal formula can target both reproductive and metabolic defects simultaneously. Therefore, further investigation into Chinese herbal medicine in the treatment of PCOS is warranted.

Topics: Androgens; Berberine; Drugs, Chinese Herbal; Female; Ginsenosides; Glucosides; Humans; Insulin Resistance; Monoterpenes; Phenanthrenes; Phytotherapy; Polycystic Ovary Syndrome; Resveratrol; Stilbenes; Theca Cells

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Biomarkers; Blood Glucose; Disease Models, Animal; Enzyme Activation; Fructose; Glucosides; Glycogen; Insulin; Insulin Resistance; Lipids; Lipogenesis; Liver; Male; Monoterpenes; Non-alcoholic Fatty Liver Disease; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction

In this study, we evaluated the effects of paeoniflorin (PF) on palmitate (PA)-induced insulin resistance and explored the potential molecular mechanisms in HepG2 cells. HepG2 cells were pre-treated with 3μM, 30μM, or 100μM PF for 1h followed by immediate stimulation with 0.25mM palmitate for 24h to induce hepatic steatosis. PF treatment could decrease PA-induced intracellular lipid deposition via inhibiting de novo lipid synthesis. PF treatment also restored insulin sensitivity by suppressing the activation of Rho kinase (ROCK) and the expression of serine phosphorylation of insulin receptor substrate (IRS)-1, thereby promoting Akt and glycogen synthase kinase (GSK)-3β phosphorylation. These results suggest that PF alleviates PA-induced hepatic steatosis and insulin resistance in HepG2 cells. Furthermore, the effect of PF may be associated with its role in inhibiting de novo lipid synthesis and in regulating the ROCK/IRS/Akt signalling pathways.

Topics: Cell Line, Tumor; Fatty Liver; Glucose; Glucosides; Glycogen Synthase Kinase 3 beta; Hep G2 Cells; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Lipid Metabolism; Lipids; Monoterpenes; Palmitates; Phosphorylation; Proto-Oncogene Proteins c-akt; rho-Associated Kinases; Signal Transduction

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver diseases. This study sought to evaluate the insulin-sensitizing effect of paeoniflorin (PF) on high-fat diet-induced NAFLD and possible molecular mechanisms. Male Sprague Dawley rats were fed a high-fat diet (HFD) for 10 weeks to establish the NAFLD model, and PF (20 mg/kg/d) was gavaged to the NAFLD rats for another four weeks. Our results demonstrated that HFD resulted in hepatocellular ballooning, micro-/macrovesicular steatosis, and oxidative stress in the liver, accompanied by increased serum total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels and homeostasis model of insulin resistance (HOMA-IR) index. PF treatment improved the biochemical and histopathological changes in NAFLD rats. Moreover, we also found that PF could inhibit lipid ectopic deposition via regulating lipid metabolism (inhibiting lipid synthesis of cholesterol and de novo pathway), and exert insulin sensitizing effect by regulating the insulin signaling pathway IRS/Akt/GSK3β and anti-oxidation. The study findings suggest that PF has therapeutic potential against NAFLD and that it acts through multiple signaling pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cytochrome P-450 CYP2E1; Diet, High-Fat; Disease Models, Animal; Glucosides; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Male; Monoterpenes; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats; Reactive Oxygen Species; Signal Transduction

TNFα plays an important role in the adipocyte dysfunction, including lipolysis acceleration, insulin resistance and changes of adipokines. Recently, we showed that paeoniflorin attenuates adipocyte lipolysis and inhibits the phosphorylation of ERK, JNK, IKK stimulated by TNFα. However, the effects of paeoniflorin on adipocytes insulin resistance and changes of adipokines remain unknown. The aim of the current study was to investigate the role of paeoniflorin in preventing insulin resistance or inflammation in 3T3-L1 adipocytes treated with TNFα. Our results showed that paeoniflorin restored insulin-stimulated [(3)H]2-DOG uptake, which was reduced by TNFα, with concomitant restoration in serine phosphorylation of IRS-1 and insulin-stimulated phosphorylation of AKT in adipocytes. Paeoniflorin attenuated TNFα-mediated suppression of the expressions of PPARγ and PPARγ target genes, and the improvement of paeoniflorin on TNFα-induced insulin resistance was attenuated by GW9662, an antagonist of PPARγ activity. Moreover, paeoniflorin could inhibit the expressions and secretions of IL-6 and MCP-1 from adipocytes induced by TNFα. These results, together with our previous data, indicate that paeoniflorin exerts a beneficial effect on adipocytes to prevent TNFα-induced insulin resistance and inflammatory adipokine release. Our studies provide important evidence for an ability of paeoniflorin in amelioration of TNFα-induced adipocyte dysfunction, which would be helpful to clarify its potential role in the treatment of obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Anilides; Animals; Benzoates; Bridged-Ring Compounds; Chemokine CCL2; Drugs, Chinese Herbal; Gene Expression; Glucose; Glucosides; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukin-6; Mice; Monoterpenes; Obesity; Paeonia; Phosphorylation; PPAR gamma; Proto-Oncogene Proteins c-akt; Tumor Necrosis Factor-alpha

Obesity is associated with a state of chronic, low-grade inflammation. It is considered that the paracrine loop involving free fatty acid (FFA) and tumor necrosis factor (TNF)α between adipocytes and macrophages establishes an inflammatory vicious cycle that augments the inflammatory changes and insulin resistance in obese adipose tissue. Paeoniflorin (PF), one of the major components of Paeony root, has been shown to have anti-inflammatory effects in vivo. We investigated the effect of PF on the production of FFA and TNFα in the interaction between adipocytes and macrophages. Coculture of 3T3-L1 adipocytes and RAW 264.7 macrophages markedly enhanced the production of TNFα and FFA compared with the control cultures, however, treatment with PF dose-dependently inhibited the production. We further examined the effects of PF on TNFα-stimulated adipocyte lipolysis and on FFA-induced macrophage TNFα expression. PF inhibited TNFα-stimulated adipocyte lipolysis in a dose-dependent manner, which was compatible with suppressed phosphorylation of TNFα-activated ERK1/2 and preserved downregulation of perilipin. Palmitate, one of the most important saturated FFAs, induced macrophage TNFα upexpression, but PF partially attenuated the effect. These results indicate that PF exhibits anti-inflammatory properties by inhibiting the vicious cycle between adipocytes and macrophages. PF may be useful for ameliorating the inflammatory changes in obese adipose tissue.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bridged-Ring Compounds; Cell Line; Fatty Acids, Nonesterified; Glucosides; Inflammation; Insulin Resistance; Lipolysis; Macrophages; Mice; Monoterpenes; Tumor Necrosis Factor-alpha