Consuming a Western diet for two weeks suppresses fetal genes in mouse hearts

Abstract

Diets high in sugar and saturated fat (Western diet) contribute to obesity and pathophysiology of metabolic syndrome. A common physiological response to obesity is hypertension, which induces cardiac remodeling and hypertrophy. Hypertrophy is regulated at the level of chromatin by repressor element 1-silencing transcription factor (REST), and pathological hypertrophy is associated with reexpression of a fetal cardiac gene program. Reactivation of fetal genes is commonly observed in hypertension-induced hypertrophy; however, this response is blunted in diabetic hearts, partially due to upregulation of the posttranslational modification O-linked-β-N-acetylglucosamine (O-GlcNAc) to proteins by O-GlcNAc transferase (OGT). OGT and O-GlcNAc are found in chromatin-modifying complexes, but it is unknown whether they play a role in Western diet-induced hypertrophic remodeling. Therefore, we investigated the interactions between O-GlcNAc, OGT, and the fetal gene-regulating transcription factor complex REST/mammalian switch-independent 3A/histone deacetylase (HDAC). Five-week-old male C57BL/6 mice were fed a Western (n = 12) or control diet (n = 12) for 2 wk to examine the early hypertrophic response. Western diet-fed mice exhibited fasting hyperglycemia and increased body weight (P < 0.05). As expected for this short duration of feeding, cardiac hypertrophy was not yet evident. We found that REST is O-GlcNAcylated and physically interacts with OGT in mouse hearts. Western blot analysis showed that HDAC protein levels were not different between groups; however, relative to controls, Western diet hearts showed increased REST and decreased ANP and skeletal α-actin. Transcript levels of HDAC2 and cardiac α-actin were decreased in Western diet hearts. These data suggest that REST coordinates regulation of diet-induced hypertrophy at the level of chromatin.

Nutrient regulation of gene expression by O-GlcNAcylation of chromatin

“…In fact, western-diet or exercise modulates OGT’s association with epigenetic writers in mice [42,43]. Since epigenetic changes can be inherited during cell division and maintained as an acquired phenotype, our eating habits and even life style have the potential to be imprinted in our genes.…”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…These observations are in line with the downregulated transcript levels of HDAC2 and cardiac α-actin in murine hearts following a two-week Western diet feeding. Further study revealed that repressor element 1-silencing transcription factor REST orchestrates the level of chromatin in diet-induced hypertrophy (Medford et al, 2014). Deacetylation and dephosphorylation of histone H3 has also been reported in the hearts of diabetic Sprague-Dawley rats, responsible for changes in gene expression in the extracellular matrix (ECM) and cardiac hypertrophy (Gaikwad et al, 2010).…”

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

“…73,79) reported for the first time that mSin3A and REST are O-GlcNAcylated in mouse heart; moreover, not only are HDAC1, HDAC2, HDAC4, and HDAC5 O-GlcNAcylated, but also OGT interacts with all of these proteins. Although there was no impact of a high fat/high sugar diet on cardiac O-GlcNAc levels (79), acute exercise decreased the OGT/REST association in non-diabetic mouse hearts (73).…”