quercetin-3-o-glucuronide and Insulin-Resistance

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) related imbalance, Tau-hyperphosphorylation, and neuroinflammation, in which Aβ and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome.. AD mice model built through intracerebroventricular injection of Aβ. Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Cognitive Dysfunction; Disease Models, Animal; Gastrointestinal Microbiome; Hippocampus; Humans; Insulin Resistance; Male; Memory Disorders; Mice, Inbred C57BL; Neuroblastoma; Neurons; Neuroprotective Agents; Peptide Fragments; Quercetin; tau Proteins

An impaired capacity of adipose tissue expansion leads to adipocyte hypertrophy, inflammation and insulin resistance (IR) under positive energy balance. We previously showed that a grape pomace extract, rich in flavonoids including quercetin (Q), attenuates adipose hypertrophy. This study investigated whether dietary Q supplementation promotes adipogenesis in the epididymal white adipose tissue (eWAT) of rats consuming a high-fat diet, characterizing key adipogenic regulators in 3T3-L1 pre-adipocytes. Consumption of a high-fat diet for 6 weeks caused IR, increased plasma TNFα concentrations, eWAT weight, adipocyte size and the eWAT/brown adipose tissue (BAT) ratio. These changes were accompanied by decreased levels of proteins involved in angiogenesis, VEGF-A and its receptor 2 (VEGF-R2), and of two central adipogenic regulators, i.e. PPARγ and C/EBPα, and proteins involved in mature adipocyte formation, i.e. fatty acid synthase (FAS) and adiponectin. Q significantly reduced adipocyte size and enhanced angiogenesis and adipogenesis without changes in eWAT weight and attenuated systemic IR and inflammation. In addition, high-fat diet consumption increased eWAT hypoxia inducible factor-1 alpha (HIF-1α) levels and those of proteins involved in adipose inflammation (TLR-4, CD68, MCP-1, JNK) and activation of endoplasmic reticulum (ER) stress, i.e. ATF-6 and XBP-1. Q mitigated all these events. Q and quercetin 3-glucoronide prevented TNFα-mediated downregulation of adipogenesis during 3T3-L1 pre-adipocytes early differentiation. Together, Q capacity to promote a healthy adipose expansion enhancing angiogenesis and adipogenesis may contribute to reduced adipose hypertrophy, inflammation and IR. Consumption of diets rich in Q could be useful to counteract the adverse effects of high-fat diet-induced adipose dysfunction.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Antioxidants; Body Weight; Diet, High-Fat; Hypertrophy; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Insulin Resistance; Male; Mice; Obesity; Quercetin; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Quercetin is a dietary flavonoid whose role in the regulation of the activity of insulin remains controversial. Our study aimed to investigate how quercetin and its major metabolite quercetin-3-glucuronide (Q-3-G) regulate insulin-mediated glucose disposal in skeletal muscle under normal and inflammatory conditions.. Under normal conditions, quercetin impaired glucose and insulin tolerance and attenuated insulin-mediated phosphorylation of Akt substrate of 160 kDa (AS160) and TBC1D1 without affecting Akt activity in male Institute of Cancer Research (ICR) mice. However, under inflammatory conditions, quercetin exhibited an opposite effect in these animals. In C2C12 cells, quercetin also decreased insulin-stimulated AS160 and TBC1D1 phosphorylation and glucose uptake in the absence of an inflammatory insult, whereas it improved the action of insulin under inflammatory conditions. Knockdown of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) blocked the differential effects of quercetin under both conditions. Unlike quercetin, Q-3-G had no influence on insulin-induced phosphorylation of AS160 and TBC1D1 and glucose uptake in C2C12 myotubes under normal conditions. Q-3-G displayed a similar regulation with quercetin in glucose disposal under inflammatory conditions.. Quercetin suppressed insulin-mediated glucose disposal in skeletal muscle tissue/cells under normal conditions while it ameliorated impaired glucose uptake under inflammatory conditions with activation of AMPK. In contrast, Q-3-G ameliorated insulin resistance in skeletal cells under inflammatory conditions without affecting glucose disposal under normal conditions.

Topics: AMP-Activated Protein Kinases; Animals; Enzyme Activation; Glucose; GTPase-Activating Proteins; Insulin; Insulin Resistance; Male; Mice, Inbred ICR; Muscle, Skeletal; Myositis; Phosphorylation; Quercetin

Quercetin represents antioxidative/antiinflammatory flavonoids widely distributed in the human diet. Quercetin is efficiently metabolized during absorption to quercetin-3-O-glucuronide. This study aims to parallelly investigate whether quercetin and quercetin-3-O-glucuronide exert protection against palmitate (PA)-induced inflammation and insulin resistance in the endothelium.. Human umbilical vein endothelial cells were pretreated with quercetin and quercetin-3-O-glucuronide for 30 min, and then incubated with 100 μM PA for 30 min or 12 h with or without insulin. PA stimulation led to reactive oxygen species (ROS) production with collapse of mitochondrial membrane potential (Δψm). Quercetin and quercetin-3-O-glucuronide inhibited ROS overproduction and effectively restored Δψm, demonstrating their chemorpotection of mitochondrial function through antioxidative actions. Also, quercetin and quercetin-3-O-glucuronide inhibited ROS-associated inflammation by inhibition of interleukin-6 and tumor necrosis factor-α production with suppression of IKKβ/NF-κB phosphorylation. Inflammation impaired insulin PI3K signaling and reduced insulin-mediated nitric oxide (NO) production. Quercetin and quercetin-3-O-glucuronide facilitated PI3K signaling by positive regulation of serine/tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and restoration of downstream Akt/eNOS activation, leading to an increased insulin-mediated NO level.. The above-mentioned evidence indicates that quercetin and quercetin-3-O-glucuronide are equally effective in inhibiting ROS-associated inflammation and ameliorating insulin resistant endothelial dysfunction by beneficial regulation of IRS-1 function.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; I-kappa B Kinase; Inflammation; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukin-6; NF-kappa B; Nitric Oxide Synthase Type III; Oxidative Stress; Palmitates; Phosphorylation; Proto-Oncogene Proteins c-akt; Quercetin; Reactive Oxygen Species; Tumor Necrosis Factor-alpha