Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation

We exposed three mouse strains to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. Comprehensive methylation and transcriptomic analysis found overlapping but also highly divergent changes in DNA methylation and gene expression, with pathway analysis suggesting a strategy for strain-specific targeted pharmacologic intervention of upstream regulators. Administeration of the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway resulted in genotype-specific protection against dietary effects in BL6 as predicted by our epigenetic analysis. Overall design: WGBS and RNA-Seq was performed on BL6, A/J, and NOD mice fed Standard or American diets. Some mice were also administered DMSO vehicle or the FXR agonist GW4064.