Abstract
Epigenetic modifications alter transcriptional activity and contribute to the effects of environment on the individual risk of obesity and Type 2 Diabetes (T2D). Here, we have estimated the in vivo effect of a fat-enriched diet (HFD) on the expression and the epigenetic regulation of the Ankyrin repeat domain 26 (Ankrd26) gene, which is associated with the onset of these disorders. In visceral adipose tissue (VAT), HFD exposure determined a specific hyper-methylation of Ankrd26 promoter at the −436 and −431 bp CpG sites (CpGs) and impaired its expression. Methylation of these 2 CpGs impaired binding of the histone acetyltransferase/transcriptional coactivator p300 to this same region, causing hypo-acetylation of histone H4 at the Ankrd26 promoter and loss of binding of RNA Pol II at the Ankrd26 Transcription Start Site (TSS). In addition, HFD increased binding of DNA methyl-transferases (DNMTs) 3a and 3b and methyl-CpG-binding domain protein 2 (MBD2) to the Ankrd26 promoter. More importantly, Ankrd26 down-regulation enhanced secretion of pro-inflammatory mediators by 3T3-L1 adipocytes as well as in human sera. Thus, in mice, the exposure to HFD induces epigenetic silencing of the Ankrd26 gene, which contributes to the adipose tissue inflammatory secretion profile induced by high-fat regimens.
Highlights
Epigenetic modifications alter transcriptional activity and contribute to the effects of environment on the individual risk of obesity and Type 2 Diabetes (T2D)
Treatment with HFD for 22 weeks led to a significant decrease in both Ankrd[26] mRNA (p < 0.001) and protein (p < 0.01) levels in obese mice compared with controls (Fig. 1a and b)
The Ankrd[26] gene expression was assessed in vitro by exposing 3T3-L1 adipocytes to either palmitate or oleate, representing saturated and unsaturated fatty acid species, which are abundant in the HFD, or alternatively to leptin, whose levels raise through obesity development[22]
Summary
Epigenetic modifications alter transcriptional activity and contribute to the effects of environment on the individual risk of obesity and Type 2 Diabetes (T2D). We have estimated the in vivo effect of a fat-enriched diet (HFD) on the expression and the epigenetic regulation of the Ankyrin repeat domain 26 (Ankrd26) gene, which is associated with the onset of these disorders. In visceral adipose tissue (VAT), HFD exposure determined a specific hyper-methylation of Ankrd[26] promoter at the −436 and −431 bp CpG sites (CpGs) and impaired its expression. In mice, the exposure to HFD induces epigenetic silencing of the Ankrd[26] gene, which contributes to the adipose tissue inflammatory secretion profile induced by high-fat regimens. A methylome analysis of mouse epididymal WAT (eAT)[19], the largest and easy accessible VAT depots in rodents[20,21], has identified promoter hyper-methylation of Ankrd[26] gene in HFD-fed compared to age- and sex-matched chow diet-fed mice, suggesting that Ankrd[26] gene is amenable to nutritionally-induced epigenetic modifications. We aimed at establishing whether and how HFD modulates Ankrd[26] gene expression in VAT in vivo through epigenetic processes
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