Fatty Acid Induced Hypermethylation in the Slc2a4 Gene in Visceral Adipose Tissue Is Associated to Insulin-Resistance and Obesity

Int J Mol Sci. 2023 Mar 29;24(7):6417. doi: 10.3390/ijms24076417.

Abstract

De novo lipogenesis (DNL) in visceral adipose tissue (VAT) is associated with systemic insulin sensitivity. DNL in VAT is regulated through ChREBP activity and glucose uptake through Glut4 (encoded by Slc2a4). Slc2a4 expression, ChREBP activity, and DNL are decreased in obesity, the underlying cause however remains unidentified. We hypothesize that increased DNA methylation in an enhancer region of Slc2a4 decreases Slc2a4 expression in obesity and insulin resistance. We found that SLC2A4 expression in VAT of morbidly obese subjects with high HbA1c (>6.5%, n = 35) is decreased, whereas DNA methylation is concomitantly increased compared to morbidly obese subjects with low HbA1c (≤6.5%, n = 65). In diet-induced obese (DIO) mice, DNA methylation of Slc2a4 persistently increases with the onset of obesity and insulin resistance, while gene expression progressively decreases. The regulatory impact of DNA methylation in the investigated enhancer region on SLC2A4 gene expression was validated with a reporter gene assay. Additionally, treatment of 3T3 pre-adipocytes with palmitate/oleate during differentiation decreased DNA methylation and increased Slc2a4 expression. These findings highlight a potential regulation of Slc2a4 by DNA methylation in VAT, which is induced by fatty acids and may play a role in the progression of obesity and insulin resistance in humans.

Keywords: DNA methylation; Slc2a4; diet-induced obese mice; human visceral adipose tissue; insulin resistance.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • DNA Methylation
  • Fatty Acids / metabolism
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Glycated Hemoglobin
  • Humans
  • Insulin Resistance* / genetics
  • Insulins* / genetics
  • Intra-Abdominal Fat / metabolism
  • Mice
  • Obesity, Morbid* / metabolism
  • Transcription Factors / metabolism

Substances

  • Fatty Acids
  • Glycated Hemoglobin
  • Transcription Factors
  • Insulins
  • SLC2A4 protein, human
  • Glucose Transporter Type 4
  • Slc2a4 protein, mouse