A new study, published in Nature Communications, has combined epigenome-wide association and integrative genomics to explore adipocyte DNA methylation in obesity. It was found that DNA methylation is an important determinant in obesity and its metabolic complications, including diabetes.
Obesity and diabetes
Obesity is defined as an excess of adipose tissue, which affects more than 650 million people worldwide. Affected individuals are at risk of developing obesity-induced inflammatory and metabolic disturbances, such as type 2 diabetes (T2D). DNA methylation is the first layer of epigenetic regulation and has been causally implicated in obesity and T2D. Despite this, very few studies have explored genome-wide DNA methylation in clinically relevant human cell types, such as adipocytes. This is because of the challenges associated with collecting and isolating cells from human tissues.
In the current study, a team of researchers used an integrated genomic strategy to address the limitations of previous epigenome-wide association studies (EWAS) in human adipocytes. Their aims were to (1) identify alterations in human adipocyte DNA methylation associated with extreme obesity; (2) predict potential effector transcripts of these methylation changes; (3) infer the mechanisms underlying DNA methylation-gene expression relationships.
Analysing adipose tissue
Subcutaneous and visceral adipose tissue samples were taken from individuals with extreme obesity and healthy controls. Populations of adipocytes were isolated from the tissues and used for genome-wide DNA methylation analysis. Using a subset of methylation sites and target genes, genetic association, targeted methylation sequencing and adipocyte manipulation were also performed as complementary analyses.
DNA methylation changes were found to be robustly associated with obesity – 691 markers were identified in subcutaneous adipocytes and 173 found in visceral adipocytes. These obesity-associated methylation variations were connected to transcriptomic changes in more than 500 genes, with putative methylation-transcription factor interactions identified. The causal effects of methylation on obesity-induced metabolic disturbances (including T2D) were also inferred at 59 independent markers.
DNA methylation determines obesity
The exploratory findings from the study using human adipocytes have revealed some of the mechanisms and molecular signalling pathways through which DNA methylation can impact human obesity, its metabolic consequences and T2D. The results also provide a resource of epigenomic variations and genes for furthering the understanding of the human epigenome and its role in obesity in the future.
The authors also highlight how this research may be explored further. Single-cell resolution technologies will enable future studies to explore cellular epigenetic heterogeneity, methylation and transcription dynamics and spatial microenvironments in adipose tissue.
