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Dose-Related Urinary Metabolic Alterations of a Combination of Quercetin and Resveratrol-Treated High-Fat Diet Fed Rats.

ABSTRACT: Most herbal polyphenols and flavonoids reveals multiple ameliorative benefits for obesity caused by chronic metabolic disorders. Accumulated studies have revealed that preferable therapeutic effects can be obtained through clinical combination of these two kinds of natural compounds for obesity improvement. The typical representative research was the combination of quercetin and resveratrol (CQR), in which the ratio of quercetin and resveratrol is 2:1, demonstrating a synergistic effect in anti-obesity process. Although there exists reports clarifying the mechanism of the combination of two to improve obesity from the perspective of improving adipose tissue inflammation or modulating the composition of intestinal flora, there are few further studies on the mechanism of drug action from the perspective of metabolites transformation. In this research, we mainly focused on the alterations of endogenous metabolites in rats, and analyzed the urine metabolites of obese and intervention model. Therefore, a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach was applied to assess the potential effects and mechanisms of CQR at different dosages (45, 90, and 180 mg/kg) in high fat diet (HFD)-induced obesity rats. Body weight gain and visceral fat weight were reduced by CQR, as well as blood lipid and inflammatory factor levels were increased by CQR in a dose-related manner. Urinary metabolomics revealed 22 differential metabolites related to the HFD-induced obesity, which were reversed in a dose-dependent manner by CQR, of which 8 were reversed in the 45 mg/kg CQR group, 15 were reversed in the 90 mg/kg CQR group, and 18 were reversed in the 180 mg/kg CQR group. Combined with bioinformatics and pattern recognition, the results demonstrated that the key differential metabolites were basically involved in amino acid metabolism, galactose metabolism, pantothenate and CoA biosynthesis, pyruvate metabolism and lysine degradation. In summary, our results showed significant therapeutic action by CQR administration and remarkable metabolomic changes after HFD feeding and CQR intervention. Urinary metabolomic analysis was highlighted on account of providing holistic and comprehensive insights into the pathophysiological mechanisms of the HFD-induced obesity, which also supplied clues for the future mechanism studies of CQR's anti-obesity effects.

SUBMITTER: Zhuang T

PROVIDER: S-EPMC8085560 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundObesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice.MethodsA total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT.ResultsHFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT.ConclusionOur results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity.

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Dose-Related Urinary Metabolic Alterations of a Combination of Quercetin and Resveratrol-Treated High-Fat Diet Fed Rats.

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