Glutathione Peroxidase‐4 plays a critical role in protection from metabolic syndrome and cardiac remodeling caused by diet‐induced obesity

Peroxidation of polyunsaturated fatty acids (PUFAs) generates a number of highly reactive lipid peroxidation products (LPPs), and the seleno‐enzyme glutathione peroxidase‐4 (GPx4) is an antioxidant enzyme that selectively neutralizes LPPs. To determine the contribution of LPPs to the pathogenesis of cardiomyopathy precipitated by diet‐induced obesity, male WT and litter‐mate GPx4‐deficient (GPx4 +/− ) mice were placed on a n‐6 PUFA enriched high fat high sucrose (HFHS) diet for 24 weeks, along with a control group of WT mice (CTL) fed low‐fat standard chow. At termination of diet, adipose tissue mass and glucose intolerance were markedly higher in the GPx4 +/− HFHS group compared to WT‐HFHS group, although both HFHS groups were significantly more than CTL. Blood pressure and cardiac function were not significantly different between groups, although left ventricular size and cardiomyocyte diameter was increased in WTHFHS group compared to CTL. Cardiac fibrosis was also markedly higher in both HFHS groups, but substantially more so in GPx4 +/− compared to WT. Mitochondrial O 2 consumption was higher in WT‐HFHS but not GPx4 +/− HFHS, compared to CTL. Surprisingly, the HFHS diet reduced mitochondrial H 2 O 2 by ~3fold in WT vs. CTL, but stayed similar between CTL and GPx4 +/− . These findings implicate GPx4 as a critical enzyme necessary for the heart to positively adapt to the oxidative stress induced by obesity.