DNA Methylation Changes More Slowly Than Physiological States in Response to Weight Loss in Genetically Diverse Mouse Strains

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."

Sex and genetic specific effects on behavioral, but not metabolic, responses to a high fat diet in heterogeneous stock rats

“…Interestingly, we find no evidence that genetic background affects metabolic response to HFD in HS rats. These results are surprising considering that previous work has shown a wide range of metabolic responses to HFD in inbred mouse strains, with some strains showing little to no effect while others are negatively impacted 64,65 . Genetic loci that interact with diet have also been identified in DO mice 51,53 , further suggesting that diet interacts with genetics to impact metabolic traits.…”

Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice

“…Still, in liver analysis of HFHS fed animals, gene expression analysis showed decreased PPARγ levels, consistent with recent reports showing PPARγ as target of epigenetic modifications after high-fat diets, which is demethylated and overexpressed after 12 weeks of HFD [ 55 ], and which is hypermethylated and downregulated after longer HFD feeding [ 56 ]. The HFHS diet has also been shown to promote epigenetic modifications, leading to changes in the expression of a set of genes involved in metabolism and homeostasis [ 57 , 58 ]. It is important to highlight that in all diets used in our study, KI animals presented decreased PPARγ expression, which may be intrinsic of this lineage, but also related to epigenetic modifications.…”

Epigenetics of Hepatic Insulin Resistance

“…A similar conclusion may be drawn from animal studies. In mice, HFD-induced changes in DNA methylation, chromatin modifications and accessibility were to some extent reversible following the return to a normal diet and body weight, including for H3K27ac and DNA methylation ( 219 , 220 ). This included restoration of high H3K27ac enrichment at regulatory elements containing binding sites of important hepatic TF families including HNF4, SREBP and C/EBP ( 220 ).…”

“…This included restoration of high H3K27ac enrichment at regulatory elements containing binding sites of important hepatic TF families including HNF4, SREBP and C/EBP ( 220 ). However, some hepatic DNA methylation marks induced by a high-fat, high-sucrose diet were reported to be more persistent and to revert more slowly than weight loss ( 219 ). The persistence of HFD-induced epigenetic changes may depend on the genetic background ( 221 ), as well as on the tissue type.…”