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Free Radic Biol Med. 2015 Dec;89:182-91. doi: 10.1016/j.freeradbiomed.2015.07.152. Epub 2015 Sep 29.

Antioxidant supplementation and obesity have independent effects on hepatic oxylipin profiles in insulin-resistant, obesity-prone rats.

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USDA-ARS Grand Forks Human Nutrition Research Center 2420 2(nd) Avenue North Grand Forks, ND 58203-9034, USA; Department of Chemistry, University of North Dakota, Grand Forks, ND 58201, USA. Electronic address:
USDA-ARS Western Human Nutrition Research Center, Davis, CA 95616, USA; West Coast Metabolomics Center, University of California Davis, Davis, CA 95616, USA; Department of Nutrition, University of California Davis, Davis, CA 95616, USA.


Obesity-induced changes in lipid metabolism are mechanistically associated with the development of insulin resistance and prediabetes. Recent studies have focused on the extent to which obesity-induced insulin resistance is mediated through oxylipins, derived from enzymatic and nonenzymatic lipid peroxidation. Vitamin E and vitamin C are widely used antioxidant supplements, but conflicting data exist as to whether supplementation with vitamins E and C reduces insulin resistance. The purpose of this work is (1) to test the hypothesis that supplementation with vitamin E and vitamin C prevents the development of insulin resistance and (2) to determine the extent to which antioxidant supplementation modifies obesity-induced changes in hepatic oxylipins. Using obesity-prone Sprague-Dawley rats fed a high-fat, hypercaloric diet, we found that vitamin E and C supplementation did not block the development of insulin resistance, despite increased plasma levels of these antioxidants and decreased hepatic F2-isoprostane (F2-IsoP) concentrations. The obese phenotype was associated with increased hepatic concentrations of cytochrome P450 (CYP450)-dependent linoleic acid and α-linolenic acid-derived epoxides. Antioxidant supplementation, but not obesity, decreased levels of the lipoxygenase (LOX)-dependent, arachidonic acid-derived products lipoxin A4 (LXA4), 8,15-dihydroxtetraenoate (8,15-DiHETE), and 5,15-DiHETE. Our data demonstrate that antioxidant supplementation and obesity impact hepatic LOX- and CYP450-dependent oxylipin metabolism.


Cytochrome P450; Epoxide hydrolase; Insulin resistance; Lipoxygenase; Obesity; Oxylipins; Vitamin C; α-Tocopherol

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