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Sci Rep. 2017 Jan 10;7:40220. doi: 10.1038/srep40220.

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

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Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institute of Health (NIH), Bethesda, MD 20892, USA.
Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.


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.

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