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A diet that is high in fat can lead to obesity and various other metabolic issues, like type II diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Interestingly, a diet high in fat can also induce issues like glucocorticoid resistance. There are two isoforms of the glucocorticoid receptor (GR), GRα and GRβ. The GRα isoform binds to glucocorticoids, while the GRβ isoform has a truncated ligand binding domain and has no known ligand. A glucocorticoid-resistant state is thought to be caused when GRβ is overexpressed. Our hypothesis is that elevated levels of GRβ, stemming from prolonged exposure to a high fat diet, contributes to adiposity by influencing lipid metabolism and lipogenesis leading to fat accumulation in the adipose and liver tissues. To test our hypothesis, we overexpressed GRβ (GRβ-Ad) or a control (Vec-Ad) via adenovirus delivery in mice fed a normal chow diet. Within five days, GRβ-Ad mice exhibited increased hepatic lipid accumulation. Western blot analysis demonstrated a significant increase (p-value <0.05) in fatty acid synthase (FAS) expression in GRβ-Ad livers, accompanied by remodeling of hepatic lipid content as indicated through mass spectrometry lipidomic analysis. Further analysis of the data indicated elevated levels of monoacylglyceride lipid species and certain long-chain triacylglycerides and diacylglycerides in the GRβ-Ad livers. mRNA analysis of the GRβ-Ad livers revealed a significant increase (p-value <0.05) of Carbohydrate-responsive element-binding protein (ChREBP), peroxisome proliferator-activated receptor (PPAR) γ, and Cyp2j6, suggesting increased de novo lipogenesis and eicosanoid synthesis. These findings suggest that glucocorticoid resistance, due to increase GRβ expression drives de novo lipogenesis and increases eicosanoid synthesis, possibly through synergism with PPARγ. Uncovering the specific functions of the GRβ isoform and glucocorticoid resistance could be helpful in developing treatments for individuals with obesity and obesity-related comorbidities. This work was supported by the National Institutes of Health R01DK121797 (T.D.H.J.) and R01DA058933 (T.D.H.J.).
Martinez et al. (Fri,) studied this question.