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

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

PROVIDER: PRJNA891340 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21937600_1.fastq.gz	Fastqsanger.gz
	SRR21937600_2.fastq.gz	Fastqsanger.gz
	SRR21937601_1.fastq.gz	Fastqsanger.gz
	SRR21937601_2.fastq.gz	Fastqsanger.gz
	SRR21937602_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

| S-EPMC10621921 | biostudies-literature

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

Project description: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.

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PHARMACOLOGICAL INHIBITION AND REVERSAL OF PANCREATIC ACINAR DUCTAL METAPLASIA

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PHARMACOLOGICAL INHIBITION AND REVERSAL OF PANCREATIC ACINAR DUCTAL METAPLASIA

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Generalized reversal of glial and neurovascular cell transcriptomic aging signatures by glucagon-like peptide-1 receptor agonist

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Transcription profiling of Xenopus hybrid sex reversal experiment

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Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.

Project description:ObjectivesActivation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters.MethodsWild-type (WT), Tgr5-/-, Fxr-/-, Apoe-/- and Shp-/- mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders.ResultsINT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα) as novel FXR-regulated genes. FXR inhibited PPARγ expression by inducing small heterodimer partner (SHP) whereas the inhibition of CEBPα by FXR was SHP-independent.ConclusionsBA receptor activation can reverse obesity, NAFLD, and atherosclerosis by specific activation of FXR or TGR5. Our data suggest that, compared to activation of FXR or TGR5 only, dual activation of both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders.

| S-EPMC5870099 | biostudies-literature

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