Graduate Thesis Or Dissertation

Metabolic effects in C57BL/6J mice fed a high-fat diet supplemented with Pinot noir juice and wine extract or quercetin, ellagic acid and resveratrol

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  • Moderate wine consumption, particularly pigment-rich red wine, is thought by many to be beneficial for the cardiovascular system. Both ethanol and phytochemicals are thought to contribute to this cardioprotective property. Metabolic disturbances associated with overconsumption of food are related to the initiation and progression of many chronic diseases, and cardiovascular disease is one of the most severe consequences. This research investigated the metabolic improvements contributed by Pinot noir wine and grape extracts (PWE and PGE), as well as by a set of selected grape phytochemicals. The first study was a rodent feeding study using C57BL/6J mice. When fed a high-fat diet, mice became hyperphagic and obese and metabolic disease ensued. Fifty-six, 6-week old male C57BL/6J mice were randomly divided into 7 experimental groups (n=8 each) fed the following diets: Low-fat (10% of energy from fat), High-fat (HF, 60% of calories from fat), and HF diet enriched with various phytochemicals. Phytochemicals supplemented to HF were: 0.2% (w/w) PWE, PGE, quercetin, ellagic acid, or 0.1% (w/w) resveratrol. Fasting glucose and aspects of physical performance were measured during the feeding study and serum lipids, hormones and cytokine levels were determined post-mortem. In the absence of reduced weight gain, various groups of high-fat-fed mice provided with grape or wine extract and/or grape phytochemicals exhibited reduced fasting glucose levels, enhanced strength, balance, and endurance, as well as reduced serum inflammatory factors. Qualitatively, a review of liver tissue sections demonstrated a reduction in lipid accumulation in hepatocytes from animals fed diets supplemented with grape and wine extracts and phytochemicals. Analysis of liver gene expression related to lipid and glucose homeostasis suggested activation of nuclear hormone receptors including PPARs, PXR, CAR and the Keap1/Nrf-2 pathway. To investigate further, we conducted a cell culture study on HepG2 cells, which were treated with a wine or grape extracts or with purified phytochemicals for 24 hours alone with 1000uM oleic acid. Quercetin, ellagic acid and resveratrol lowered HepG2 cell lipid accumulation by 26, 22 and 51%, respectively, as indicated by Oil Red O staining, and were consistent with red color indication from microscopic images acquired. However, wine and grape extracts failed to produce a reduction in cellular lipid content. We observed favorable metabolic and physical effects in mice fed wine and grape extracts as well as purified phytochemicals. The in vivo health benefits of purified phytochemicals were also confirmed in cell culture study. However, the extent of metabolic improvement sometimes differed among extracts and phytochemicals indicating different potent of the selected phytochemicals and a synergistic or antagonistic effect of extract components in specific metabolic activities. In the future, mechanistically, analysis of gene expression in cell culture and microarray analysis as well as metabolomics screening of in vivo studies are needed to demonstrate possible pathways involved; these pathways could be confirmed in gene knockout mouse models. In a similar study, other compounds present in wine and grapes can be investigated to determine which best impact metabolic improvements.
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