Alterations of the Fetal Primate Epigenome due to Maternal High Fat Diet Exposure Are Reversed in Subsequent Offspring with Cessation of High Fat Diet.

Abstract

The most recent report from the CDC shows that more than one third of American adult women are obese. The Developmental Origins Hypothesis postulates that potentially adverse conditions in utero, such as exposure to a maternal high fat diet and maternal obesity, are associated with fetal alterations, rendering susceptibility to adult metabolic disorders. We have previously reported in a non-human primate model that exposure to a maternal high fat diet results in both pathological and epigenetic changes to the fetal liver. We have shown that high fat diet exposure results in non-alcoholic fatty liver disease, concomitant with covalent modifications to fetal hepatic chromatin structure, specifically increasing histone H3 lysine 14 acetylation (H3K14ac) levels. We now show that cessation of the high fat diet during pregnancy, even in the face of persistent maternal obesity, returns acetylation levels to those of control diet animals (n=6/ group). We also show that this increased acetylation correlates with the reprogramming of several metabolic and circadian regulatory genes. The expression of Npas2, a peripheral circadian transcription factor, is disrupted in fetal hepatic tissue from animals exposed to a maternal high fat diet, returning to those of control diet upon high fat diet cessation. We also report the disruption of other circadian genes regulated by Npas2, such as Per1 and Reverb-alpha in the high fat diet exposed animals. Extensive analysis of the Npas2 promoter region shows that DNA methylation levels do not differ due to maternal diet. However, using chromatin immunoprecipitation of an important regulatory region of the Npas2 promoter, we find enrichment of H3K14ac in animals exposed to a high fat diet compared with those on a control diet. This enrichment is lost from the diet reverted group. We conclude that H3K14ac levels are perturbed by maternal high fat diet exposure, which correlates with altered gene expression. We find that reversion to a control diet, even with persistent maternal obesity, helps to attenuate some epigenomic and circadian perturbations. (platform)