DNA Methylation Implicated in Human Obesity and Diabetes DNA Methylation Implicated in Human Obesity and Diabetes

The study covered in this summary was published in medRxiv as a preprint and has not yet been peer reviewed.

Key Takeaways

  • A series of exploratory studies in human adipocytes indicate that DNA methylation is an important determinant of human obesity and its metabolic complications.

  • Altered DNA methylation may impact adipocyte cellular functions through genomic and molecular mechanisms.

Why This Matters

  • Previous attempts to identify causal associations between DNA methylation and both obesity and type 2 diabetes have been hindered by challenges in collecting and isolating cells from human tissue.

  • Recent data suggest that manipulation of DNA methylation enzymes in adipocytes can induce or prevent obesity and type 2 diabetes through cellular effects on energy expenditure and insulin sensitivity.

Study Design

  • Combined epigenome-wide association and integrative genomics investigations of the impact of subcutaneous and visceral adipocyte DNA methylation variations in extreme human obesity were conducted.

  • Subcutaneous and visceral adipose tissue samples were collected intraoperatively from people with extreme obesity and healthy controls (mean difference of approximately 20 kg/m2 in body mass index), and adipocyte populations were isolated.

  • Genome-wide DNA methylation was characterized in 190 subcutaneous and visceral adipose samples from obese and control populations, in separate discovery and replication cohorts.

Key Results

  • The 691 subcutaneous adipocyte sentinel sites had a median 5.8% (range, 1.1%-17.9%) difference in methylation between the group with obesity and controls, and were systematically hypomethylated in the group with obesity.

  • The 173 visceral sentinels had a median methylation difference of 7.9% (range, 2.9%-21.5%) between obese cases and controls, and visceral adipocyte sentinels were also preferentially hypomethylated in obesity.

  • Integration of DNA methylation findings with adipocyte-specific transcriptomic and chromosomal interaction datasets and cross-tissue enhancer-promoter catalogues allowed for statistical and functional connection of extreme obesity-associated methylation variations to transcriptomic changes at more than 500 target genes.

  • In a Mendelian randomization analysis using 588 whole adipose tissue samples, causal effects were inferred for adipocyte DNA methylation on obesity or obesity-induced metabolic disturbances at 28 independent genomic loci.

  • In a cellular model of adipogenesis, knockdown of two target genes — PRRC2A linked to central adiposity, insulin resistance, and type 2 diabetes, and LIMD2 linked to obesity, central adiposity, and type 2 diabetes — both significantly reduced lipid accumulation during adipocyte differentiation, with a greater effect observed with PRRC2A versus LIMD2 knockdown.

Limitations

  • None specified.

Disclosures

  • Study funding: Medical Research Council UK, Wellcome Trust, and the National Institute for Health Research Imperial Biomedical Research Centre.

  • Author disclosures: None.

This is a summary of a preprint research study, “Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes,” by Liam McAllan, PhD, of the Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, UK, and the MRC London Institute of Medical Sciences, provided to you by Medscape. The study has not yet been peer reviewed.