Peroxiredoxin 6 Is a Key Antioxidant Enzyme in Modulating the Link between Glycemic and Lipogenic Metabolism

Insulin action and often glucose-stimulated insulin secretion are reduced in obesity. In addition, the excessive intake of lipids increases oxidative stress leading to overt type 2 diabetes mellitus (T2DM). Among the antioxidative defense systems, peroxiredoxin 6 (PRDX6) is able to reduce H₂O₂ and short chain and phospholipid hydroperoxides. Increasing evidences suggest that PRDX6 is involved in the pathogenesis of atherosclerosis and T2DM, but its role in the etiopathology of obesity and its complications is still not known. Therefore, in the present study, we sought to investigate this association by using PRDX6 knockout mice (PRDX6^-/-). Metabolic parameters, like carbon dioxide (VCO₂) production, oxygen consumption (VO₂), and the respiratory exchange ratio (RER), were determined using metabolic cages. Intraperitoneal insulin and glucose tolerance tests were performed to evaluate insulin sensitivity and glucose tolerance, respectively. Liver and pancreas histochemical analyses were also evaluated. The expression of enzymes involved in lipid and glucose metabolism was analyzed by real-time PCR. Following 24 weeks of high-fat-diet (HFD), PRDX6^-/- mice showed weight gain and higher food and drink intake compared to controls. VO₂ consumption and VCO₂ production decreased in PRDX6^-/- mice, while the RER was lower than 0.7 indicating a prevalent lipid metabolism. PRDX6^-/- mice fed with HFD showed a further deterioration on insulin sensitivity and glucose-stimulated insulin secretion. Furthermore, in PRDX6^-/- mice, insulin did not suppress adipose tissue lipolysis with consequent hepatic lipid overload and higher serum levels of ALT, cholesterol, and triglycerides. Interestingly, in PRDX6^-/- mice, liver and adipose tissue were associated with proinflammatory gene upregulation. Finally, PRDX6^-/- mice showed a higher rate of nonalcoholic steatohepatitis (NASH) compared to control. Our results suggest that PRDX6 may have a functional and protective role in the development of obesity-related metabolic disorders such as liver diseases and T2DM and may be considered a potential therapeutic target against these illnesses.