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Genome-Wide Transcriptome Analysis Reveals Intermittent Fasting-Induced Metabolic Rewiring in the Liver

ABSTRACT: Intermittent fasting (IF) has been extensively reported to participate in improved energy homeostasis and metabolic switching, which in turn promotes protection against numerous age-associated metabolic diseases that have plagued the global population in recent years. Despite the observation that IF may be a plausible strategy to ameliorate these epidemiological burdens in many societies, investigation into the underlying molecular mechanisms behind these purported effects are still in their infancy. Particularly, the relationship between IF and genetic changes are poorly understood, which forms the basis of this research.

ORGANISM(S): Mus musculus

PROVIDER: GSE130127 | GEO | 2019/07/31

REPOSITORIES: GEO

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Project description:Intermittent fasting (IF) increases lifespan, decreases metabolic disease phenotypes, and cancer risk in model organisms, but the mechanisms mediating these effects are not fully characterized. In particular, the altered transcriptional programming has yet to be defined in key fasting responsive tissues such as liver from animals undergoing intermittent fasting. In this study, we employed every-other-day-fasting (EODF) in mice and high-resolution proteome analysis of liver and blood plasma as a screening tool to identify key regulated pathways with comparison to ad libitum fed animals. We observed many changes in the liver proteome abundance profile that were distinct from those observed after a single bout of fasting. Key among these were the induction by EODF of de novo lipogenesis (DNL) and cholesterol biosynthesis pathway enzymes, which were mirrored by related metabolite changes such as increased triacylglycerides and HMG-CoA in EODF liver of fed mice. Paradoxically, we also observed the up-regulation of mitochondrial proteins associated with fatty-acid beta oxidation including ACOT2, which is known to accelerate this pathway in vivo. The most surprising observation was the EODF-mediated 16-fold down-regulation of alpha-1-antitrypsin (SERPINA1E) in liver, which is an abundant plasma protein made exclusively in this tissue. Plasma proteome analysis confirmed a 3-fold decrease in SERPINA1E after 2 weeks of EODF among other significant changes such as increased levels of APOA4, a finding in common with previous human EODF intervention studies. We determined that in liver the SREBP1c and HNF4A transcription factors were playing a major role in the up-regulation of lipid/cholesterol synthesis and down-regulation of AAT, respectively. Further characterization of HNF4A function suggested a global inhibition of its ability to bind promoters of target genes in livers from EODF animals, which we hypothesize is mediated by either increased linoleic acid binding, or post translational modifications of HNF4A protein in EODF animal liver tissue. Together these data provide a comprehensive Omics resource highlighting the key changes observed during the intermittent fasting response in a model animal.

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Genome-Wide Transcriptome Analysis Reveals Intermittent Fasting-Induced Metabolic Rewiring in the Liver

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