Metaboepigenetic regulation of gene expression in obesity and insulin resistance

Variation in DNA methylation (DNAm) in adipose tissue is associated with the pathogenesis of obesity and insulin resistance. The activity of enzymes involved in altering DNAm levels is dependent on several metabolite cofactors.

To understand the role of metabolites as mechanistic regulators of epigenetic marks, we tested the association between selected plasma metabolites and DNAm levels in the adipose tissue of African Americans.

In the AAGMEx cohort (N = 256), plasma levels of metabolites were measured by untargeted liquid chromatography-mass spectrometry; adipose tissue DNAm and transcript levels were measured by reduced representation bisulfite sequencing, and expression microarray, respectively.

Among the 21 one-carbon metabolism pathway metabolites evaluated, six were associated with gluco-metabolic traits (P_FDR < 0.05, for BMI, S_I, or Matsuda index) in AAGMEx. Methylation levels of 196, 116, and 180 CpG-sites were associated (P < 0.0001) with S-adenosylhomocysteine (SAH), cystine, and hypotaurine, respectively. Cis-expression quantitative trait methylation (cis eQTM) analyses suggested the role of metabolite-level-associated CpG sites in regulating the expression of adipose tissue transcripts, including genes in G-protein coupled receptor signaling pathway. Plasma SAH level-associated CpG sites chr19:3403712 and chr19:3403735 were also associated with the expression of G-protein subunit alpha 15 (GNA15) in adipose. The expression of GNA15 was significantly correlated with BMI (β = 1.87, P = 1.9 × 10^-16) and S_I (β = -1.61, P = 2.49 × 10^-5).

Our study suggests that a subset of metabolites modulates the methylation levels of CpG sites in specific loci and, in turn, regulates the expression of transcripts involved in obesity and insulin resistance.