Abstract
Responses to a high fat, high sucrose (HFHS) diet vary greatly among inbred strains of mice. We sought to examine the epigenetic (DNA methylation) changes underlying these differences as well as variation in weight loss when switched to a low-fat chow diet. We surveyed DNA methylation from livers of 45 inbred mouse strains fed a HFHS diet for 8 weeks using reduced-representation bisulfite sequencing (RRBS). We observed a total of 1,045,665 CpGs of which 83 candidate sites were significantly associated with HFHS diet. Many of these CpGs correlated strongly with gene expression or clinical traits such as body fat percentage and plasma glucose. Five inbred strains were then studied in the context of weight loss to test for evidence of epigenetic “memory.” The mice were first fed a HFHS diet for 6 weeks followed by a low-fat chow diet for 4 weeks. Four of the five strains returned to initial levels of body fat while one strain, A/J, retained almost 50% of the fat gained. A total of 36 of the HFHS diet responsive CpGs exhibited evidence of persistent epigenetic modifications following weight normalization, including CpGs near the genes Scd1 and Cdk1. Our study identifies DNA methylation changes in response to a HFHS diet challenge that revert more slowly than overall body fat percentage in weight loss and provides evidence for epigenetic mediated “memory.”
Highlights
Epigenetic regulation, such as DNA methylation, was hypothesized and recently confirmed to play a role in the development of obesity in humans and rodents [1]
We performed reduced representation bisulfite sequencing (RRBS) on DNA isolated from liver and observed a total of 1,045,665 CpGs with 10x coverage across at least 70% of samples
In this study we asked a fundamental question regarding the epigenetic responses to different diets: what happens to DNA methylation changes in liver in response to a HFHS diet challenge and are these changes reversible when mice are fed a low-fat, weight loss diet? By identifying epigenetic changes and profiling weight loss phenotypes in a panel of genetically diverse mouse strains, we were able to evaluate this question in the context of variable gene-by-environment responses
Summary
Epigenetic regulation, such as DNA methylation, was hypothesized and recently confirmed to play a role in the development of obesity in humans and rodents [1]. Caloric restriction in humans and mice protects against aging associated pathologies like type 2 diabetes, heart disease, and hepatocellular carcinoma, while obesity increases this susceptibility [7,8,9]. These changes are known to be mediated in part by DNA methylation, a biomarker reproducibly associated with chronological aging. These variable epigenetic loci are often used to fit tissue-specific biological clocks of “epigenetic aging” in association with biometrics like body mass index (BMI) [10]. Obesity-associated DNA methylation changes have been been observed to accelerate “epigenetic aging” in the liver and are not acutely reversible by interventions like bariatric surgery [10,11,12]
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