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

Chantle R Edillor; Brian W Parks; Margarete Mehrabian; Aldons J Lusis; Matteo Pellegrini

doi:10.3389/fendo.2019.00882

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

Front Endocrinol (Lausanne). 2019 Dec 20:10:882. doi: 10.3389/fendo.2019.00882. eCollection 2019.

Authors

Chantle R Edillor¹, Brian W Parks², Margarete Mehrabian³, Aldons J Lusis^{1

3}, Matteo Pellegrini⁴

Affiliations

¹ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, United States.
² Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States.
³ Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, United States.
⁴ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States.

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."

Keywords: DNA methylation; liver; mouse strains; obesity; weight loss.

Grants and funding

T32 HL069766/HL/NHLBI NIH HHS/United States