Redox Regulation of FGF21 in an Obese “Stress‐less” Mouse Model

Abstract

BackgroundOxidative stress plays a key role in the metabolic syndrome including Type 2 Diabetes and Obesity. It is implicated that oxygen‐derived free radicals alter the function of metabolic tissues thus altering glucose and lipid homeostasis. Catalase is an antioxidant enzyme that helps to catabolize hydrogen peroxide generated by superoxide dismutation which subsequently reduces oxidative stress. The protein hormone Fibroblast Growth Factor 21 (FGF21) plays regulatory roles in lipid and glucose metabolism, and more recently, has been shown to be a novel regulator of oxidative stress giving it clinical significance in the context of Type 2 Diabetes and Obesity. FGF21 expression has been shown to increase under higher oxidative stress conditions.HypothesisWe hypothesized that excess catalase expression would deter oxidative stress mediated metabolic regulation in adipose tissue as exhibited by changes in FGF21 expression levels and insulin sensitivity.MethodsTo test this hypothesis, male control C57Bl6, Catalase transgenic (Cat‐tg) mice that expressed 3–4 fold excess catalase, as well as the newly engineered Bob‐Cat mice, which is a hybrid of Cat‐tg and the leptin resistant obese Ob‐Ob mice (study approved by MU IACUC), were fed normal chow (NC), 45% fish oil (OM3), or 45% high fat (HFD) diet for 8 weeks. Weekly body weights and food consumption were measured. ECHO‐MRI was used to analyze body fat and lean mass. HOMA‐IR was calculated based on fasting glucose and plasma insulin levels. Changes in mRNA expression of key genes regulating metabolic homeostasis (FGF‐21 and Nrf2) were measured in adipose tissue. ANOVA was used for statistical comparisons using GraphPad Prism.ResultsThe HOMO‐IR data showed that the Cat‐tg mice became insulin resistant while on the HF diet, while the C57 and Bob‐Cat mice maintained their insulin sensitivity although fat mass increased on the high fat diet across all three genotypes. Gene expression data showed a significant increase in FGF21 and Nrf2 in the Bob‐Cat mice that were on the HF and OM3 diets. There was a negative correlation between Nrf2 and FGF21.ConclusionThe results of the gene expression data and insulin homeostasis in the presence of excess antioxidants (catalase) show that proper redox balance is necessary for the signaling and function of FGF21. The correlation in FGF21 expression in the HF and OM3 diets of the Bob‐Cat and the maintenance of insulin sensitivity indicate that FGF21 acts to minimize the effects of poor nutritive conditions.Support or Funding InformationDepartment of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WVThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.