The 89th Annual Meeting of the American Association of Physical Anthropologists (2020)

Epigenetic modulation of leptin's signaling by Uncoupling Protein Polymorphisms (UCP2 - UCP3) and serum lipids


1Laboratory of Biological Anthropology, University of Kansas, 2Department of Anthropology, Western Washington University, 3Department of Anthropology, University of Kansas

April 16, 2020 , Platinum Ballroom Add to calendar

Patterns in DNA methylation are attributed to individual genotypes at distinct loci speculated to underlie gene-environment interactions. Polymorphisms in mitochondrial uncoupling protein-2 and -3 (UCP2 & UCP3) and circulating leptin levels together influence energy homeostasis and lipid metabolism. Low leptin levels defend fat storage levels in adipose tissue while UCP2 and UCP3 influence tissue specific fuel selection, lipid oxidation and metabolic pathways. Here we hypothesize that UCPs SNPs and lipid levels are promoting variation in DNA methylation along leptin’s core promoter region, thus modulating leptin’s signaling. Data obtained from previous studies of 139 Kansas Mennonites (79 females/60 males) included whole exome sequences, methylation profiles for 7 CpG sites of leptin’s core promoter region, anthropometric measurements, and fasting serum lipid and leptin levels. Least-squares regression was used to test for SNP/CpG/Environmental associations. Models were sex-stratified and corrected for age and waist-hip ratio. Statistical significance was assessed at p < 0.005 and FDR < 0.10. Results suggest sexual dimorphism in accumulation of methyl groups along leptin’s promoter. Among males, LDL and HDL levels and multiple SNPs in UCP2 and UCP3 (rs660339, rs2075577, and rs2734828; p < 0.005) are associated with differential methylation patterns in CpG sites that may increase resting metabolic rate, not storage. In females methylation of the site modulating the last step in adipocyte maturation is associated with circulating blood leptin levels and UCP2 (rs660627; p < 0.005). These findings suggest epigenetic regulation consistent with dimorphic cold adaptation: females increase adipose stores; males increase metabolic response.