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

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach. Author summary: Metabolic syndrome is a major contributor to worldwide morbidity and mortality. This disorder is influenced by both genetics and environmental exposures, particularly diet. Such an effect, known as a "gene-by-diet" interaction, suggests that optimal dietary recommendations and therapeutic interventions for treating metabolic syndrome may differ dramatically between genetic sub-populations. Here, we have analyzed genetically distinct mouse strains which exhibit varying degrees of metabolic syndrome in response to a high-fat, high-carbohydrate American diet. While similar biological processes were affected by the change in diet in all three strains, we observed a strain-unique disruption of epigenetic and transcriptional regulation of certain molecular pathways, allowing for a strain-specific therapeutic platform aimed to re-establish normal functionality of one of these disrupted molecular pathways. Indeed, application of the chosen drug significantly decreased the observed metabolic effects of the American diet in only the predicted strain while the other tested strain exhibited increased activity of inflammatory response genes, demonstrating the strain-specificity of this drug's efficacy as well as its associated toxicities. This pilot study highlights the value of precision therapeutics in the treatment of metabolic syndrome and underscores the advantage of using multiple genetically distinct strains of mice in preclinical drug trials to help identify genetic dependencies in efficacy and toxicity. [ABSTRACT FROM AUTHOR]