Specific CpG hyper-methylation leads to Ankrd26 gene down-regulation in white adipose tissue of a mouse model of diet-induced obesity

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.

Supplementation with Resveratrol, Piperine and Alpha-Tocopherol Decreases Chronic Inflammation in a Cluster of Older Adults with Metabolic Syndrome

“…These findings confirm the significant activation of inflammatory processes by the innate and adaptive immune systems [ 31 ] in obesity, which constitute risk factors for increased insulin resistance and diabetes. In brief, lipid accumulation in adipose tissue in obese patients triggers an inflammatory response, resulting in an increased release of several cytokines [ 32 , 33 ]. It has also been evidenced that dyslipidemia induces an inflammatory response due to the activation of the immune system.…”

Epigenetic modifications of the Zfp/ZNF423 gene control murine adipogenic commitment and are dysregulated in human hypertrophic obesity

“…Zfp423 promoter (−1037/−1002) was amplified by PCR and cloned into the firefly luciferase reporter pCpGfree-promoter-Lucia vector (InvivoGen). A one-step PCR-based mutagenesis technique was used to generate site-specific mutation [ 28 ] and produce a mutated construct. One complementary pair of primers was designed that contained the desired mutation, replacing the cytosine at position −1016 with adenine.…”

Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes

“…As has already been discussed in the review, WAT is the main site where lowgrade systemic inflammation begins (Weisberg et al, 2003;Xu et al, 2003). Accumulation of lipids that occurs in AT during obesity triggers an inflammatory response that results in an increased secretion of several inflammatory cytokines (Haase et al, 2014;Raciti et al, 2017). Such molecules can also activate JNK and NF-κB signaling pathways in the liver and skeletal muscle, thus inhibiting systemic insulin signaling (Hotamisligil et al, 1993;Ciccarelli et al, 2016).…”