Persistent Chromatin Modifications Induced by High Fat Diet*

Abstract

Obesity is a highly heritable complex disease that results from the interaction of multiple genetic and environmental factors. Formerly obese individuals are susceptible to metabolic disorders later in life, even after lifestyle changes are made to mitigate the obese state. This is reminiscent of the metabolic memory phenomenon originally observed for persistent complications in diabetic patients, despite subsequent glycemic control. Epigenetic modifications represent a potential mediator of this observed memory. We previously demonstrated that a high fat diet leads to changes in chromatin accessibility in the mouse liver. The regions of greatest chromatin changes in accessibility are largely strain-dependent, indicating a genetic component in diet-induced chromatin alterations. We have now examined the persistence of diet-induced chromatin accessibility changes upon diet reversal in two strains of mice. We find that a substantial fraction of loci that undergo chromatin accessibility changes with a high fat diet remains in the remodeled state after diet reversal in C57BL/6J mice. In contrast, the vast majority of dietinduced chromatin accessibility changes in A/J mice are transient. Our data also indicate that the persistent chromatin accessibility changes observed in C57BL/6J mice are associated with specific transcription factors and histone post-translational modifications. The persistent loci identified here are likely to be contributing to the overall phenotype and are attractive targets for therapeutic intervention.Obesity and related metabolic diseases result from both genetic and environmental factors, such as exercise and diet. However, the molecular mechanisms that contribute to disease progression remain unclear. Intriguingly, previously obese individuals have increased mortality compared with normal individuals, despite therapeutic intervention (1). This is reminiscent of "metabolic memory," a phenomenon originally described in diabetic patients in which micro-and macrovascular complications develop long after blood glucose is normalized (2-4). It has been hypothesized that epigenetic modifications, such as alterations to the chromatin and non-sequence changes to DNA, including DNA methylation, can contribute to this "metabolic memory" (5-7).It is now well established that epigenetic modifications can contribute to disease progression (8). One manner by which external environmental factors can influence molecular pathways is through alterations to chromatin. It has been shown that high fat (HF) 2 diet leads to chromatin accessibility changes in the liver tissue of mice (9). Intriguingly, the genomic loci with the greatest degree of diet-induced chromatin accessibility changes are largely strain-specific, indicating a role for genetics in this response (9). Previous studies examining diet-induced metabolic dysfunctions have shown that mice that transition from HF to diets that are low in fats do not completely revert to the same state as mice only maintained on low fat diets (10). The data indicate th...

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

“…It has previously been suggested that HFD-induced chromatin remodeling (probed by FAIRE-seq) in the mouse liver genome persists after weight loss6. To investigate whether HFD-induced H3K27Ac changes are maintained after weight loss, we profiled H3K27Ac in three livers from HFD-chow mice and compared those to Chow-chow mice.…”

“…It has been shown that a shift from HFD to regular chow reverses the dysregulated circadian clock at a transcriptional20 as well as at a behavioral level21, suggesting that the change of diet can reverse HFD-provoked deregulation of hepatic gene transcription and ultimately normalize lipid and glucose metabolism42. However, a recent study has suggested that significant changes of chromatin organization and gene transcription in the liver may persist after a shift from HFD to regular chow diet in DIO mice6. However, that study did not achieve a complete normalization of the weight and hepatic TG accumulation after diet reversal6.…”

“…Moreover, despite successful control of metabolic dysfunction, such as type 2 diabetes, the remaining metabolic memory leads to increased risk of metabolic diseases234. Recent studies have suggested that epigenetic factors may contribute to the metabolic memory in liver tissue56, indicating that efforts to identify and modify these factors could be beneficial for metabolic intervention and help prevent relapse after treatment.…”

“…This process is controlled by a range of molecular mechanisms, including change of the hepatic transcriptional program51617. Hepatosteatosis is reversible18, yet it has been suggested that DIO in rodents followed by weight loss leaves persistent changes in hepatic chromatin organization (probed by FAIRE-seq) and persistent pattern of gene expression6. In agreement with these studies, it has been reported that hepatic DNA methylation in humans is changed by obesity, and weight loss by bariatric surgery does not fully reverse obesity-associated DNA methylation19.…”

Prenatal Dexamethasone and Postnatal High-Fat Diet Decrease Interferon Gamma Production through an Age-Dependent Histone Modification in Male Sprague-Dawley Rats

“…A study of site-specific histone modifications can provide us with a more precise mechanism for GC exposure. A HF diet could also lead to persistent change in chromatin accessibility with enriched H3K9me2 in mouse liver [43]. A HF diet has also been reported to cause histones H3 and H4 hypoacetylation, H3K4 hypomethylation, and increased HDACs 1, 2, 6 binding at the leptin promoter in adipose tissue [44].…”