High fat diet-induced changes of mouse hepatic transcription and enhancer activity can be reversed by subsequent weight loss

Abstract

Epigenetic factors have been suggested to play an important role in metabolic memory by trapping and maintaining initial metabolic changes within the transcriptional regulatory machinery. In this study we fed mice a high fat diet (HFD) for seven weeks followed by additional five weeks of chow, to identify HFD-mediated changes to the hepatic transcriptional program that may persist after weight loss. Mice fed a HFD displayed increased fasting insulin levels, hepatosteatosis and major changes in hepatic gene transcription associated with modulation of H3K27Ac at enhancers, but no significant changes in chromatin accessibility, indicating that HFD-regulated gene transcription is primarily controlled by modulating the activity of pre-established enhancers. After return to the same body weight as chow fed control mice, the fasting insulin, glucose, and hepatic triglyceride levels were fully restored to normal levels. Moreover, HFD-regulated H3K27Ac and mRNA levels returned to similar levels as control mice. These data demonstrates that the transcription regulatory landscape in the liver induced by HFD is highly dynamic and can be reversed by weight loss. This provides hope for efficient treatment of early obesity-associated changes to hepatic complications by simple weight loss intervention without persistent reprograming of the liver transcriptome.

Holistic Characterization of Single Hepatocyte Transcriptome Responses to High Fat Diet

“…Gene ontology analysis of HFD-upregulated and -downregulated (LFD-upregulated) genes showed that, consistent with previous bulk gene expression studies (28)(29)(30), genes controlling lipid and fatty acid metabolism are upregulated in HFD, while genes controlling amino acid and drug catabolism are downregulated (…”

“…Importantly, PPAR is known to be activated upon stimulation with fatty acids, as they are direct ligands for transcriptional activation of PPAR (42,43). Former bulk analysis of fatty liver transcriptome also revealed that various targets of PPAR, as represented in our dataset, are strongly upregulated upon HFD challenges (28)(29)(30)45). Notably, many of these genes did not show such diet-dependent modulations in Ppara-deleted knockout mutant strains (44,45).…”

Brown adipose tissue (BAT) specific vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA-methylation

“…Treatment with the histone deacetylase inhibitor trichostatine A increased KLK7 expression in pancreatic (Panc-1) and cervical (HeLa) cancer cell lines [61]. Importantly, HFD-induced changes seem to be readily reversible after weight-loss, as reported for hepatic epigenetic changes induced after 7 weeks of HFD in mice [62], and HFD-induced DNA-hypermethylation could also be suppressed via exercise in mice [57]. DNA methylation in the promoter regions of the vaspin gene in WAT and BAT has not been investigated previously.…”

Genome-wide profiling of histone H3K27 acetylation featured fatty acid signalling in pancreatic beta cells in diet-induced obesity in mice

“…Changes in epigenetic modifications and transcriptional regulation are essential for phenotypic adaptation of cell types to environments, including high-fat diet (HFD) [15][16][17]. Since some DNA-binding proteins play a role in triggering epigenetic reprogramming in specific genomic regions [18], we hypothesised that the corresponding sequence motifs could be enriched in cis-regulatory regions with local epigenetic alterations in response to environmental stimuli.…”