Epigenetic silencing of the ANKRD26 gene correlates to the pro-inflammatory profile and increased cardio-metabolic risk factors in human obesity

Abstract

BackgroundObesity is a major worldwide threat to human health. Increasing evidence indicates that epigenetic modifications have a major impact on the natural history of this disorder. Ankyrin Repeat Domain 26 (Ankrd26) is involved in the development of both obesity and diabetes in mice and is modulated by environmentally induced epigenetic modifications. This study aims at investigating whether impaired ANKRD26 gene expression and methylation occur in human obesity and whether they correlate to the phenotype of these subjects.ResultsWe found that downregulation of ANKRD26 mRNA and hyper-methylation of a specific region of the ANKRD26 promoter, embedding the CpG dinucleotides − 689, − 659, and − 651 bp, occur in peripheral blood leukocytes from obese compared with the lean subjects. ANKRD26 gene expression correlates inversely to the percentage of DNA methylation at these 3 CpG sites. Luciferase assays reveal a cause-effect relationship between DNA methylation at the 3 CpG sites and ANKRD26 gene expression. Finally, both ANKRD26 mRNA levels and CpG methylation correlate to body mass index and to the pro-inflammatory status and the increased cardio-metabolic risk factors of these same subjects.ConclusionDownregulation of the ANKRD26 gene and hyper-methylation at specific CpGs of its promoter are common abnormalities in obese patients. These changes correlate to the pro-inflammatory profile and the cardio-metabolic risk factors of the obese individuals, indicating that, in humans, they mark adverse health outcomes.

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

“…In mice, diet-induced obesity led to hypermethylation of the Ankrd26 gene (previously associated with the development of obesity and T2DM), which in turn, contributed to enhanced secretion of pro-inflammatory mediators in white adipose tissue [83]. Consistently, epigenetic silencing of the ANKRD26 gene by increased promoter methylation correlated with a pro-inflammatory profile and the presence of cardio-metabolic risk factors in peripheral leukocytes from obese individuals [84]. Transgenerational studies detected DNA methylation changes of key inflammatory genes in monocytes from neonates born of obese mothers, underlying an intrauterine epigenetic programming of immune function by maternal obesity [85].…”

Epigenetic Dysregulation of the Homeobox A5 (HOXA5) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity

“…A total of 16 Caucasian individuals (8 obese patients and 8 lean individuals) from an independent cohort recruited at the Federico II University of Naples were included in the replication analysis. The recruitment and clinical phenotyping of these subjects have also been previously described [ 9 , 11 ]. The study adhered to the Code of Ethics of the World Medical Association (Declaration of Helsinki), and was approved by the Ethics Committee of the Federico II University of Naples (ethical approval number 254/17).…”

Molecular basis of ageing in chronic metabolic diseases

“…Accordingly, approaches that are successful in counteracting obesity and ageing, such as exercise and nutritional interventions, exert their health effects by targeting cellular senescence in AT [25,26,52,87]. As epigenetic factors respond adaptively to lifestyle they may be implicated independently of age in the acquisition of a senescent phenotype [51,[88][89][90][91][92][93].…”