Impact of <i>AKR1C2</i> and <i>AKR1C3</i> single-nucleotide polymorphism rs28571848 in adipose tissues of individuals with severe obesity

Adipose tissue androgen turnover, dictated at least in part by the enzymes aldo-keto reductase 1 C type 2 (AKR1C2) and aldo-keto reductase 1 C type 3 (AKR1C3), has been linked to abdominal obesity. Recently, we investigated a single-nucleotide polymorphism (SNP) named rs28571858, that might increase <i>AKR1C2</i> and <i>AKR1C3</i> expression in human adipose tissue. Here, we studied the impact of rs28571848 on adipose tissue function and cardiometabolic health in bariatric surgery candidates. We genotyped a sample of 2,776 bariatric surgery candidates and retrospectively obtained anthropometry, blood lipid and glucose profiles, menopausal status, and medication use. In a subsample of 135 individuals (62% women, age 42 yr, body mass index of 51 kg/m²), we additionally assessed <i>AKR1C2</i> and <i>AKR1C3</i> expression in whole tissue by RT-qPCR. Features of adipose tissue dysfunction, such as mean adipocyte diameter and pericellular fibrosis, were assessed by histological staining and semiautomated image analysis. Finally, adipose tissue AKR1C family enzyme activity was measured by fluorimetry. The rs28571848 SNP affected <i>AKR1C3</i> expression in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in women only, while not altering <i>AKR1C2</i> expression in either men or women. Individuals carrying the minor allele exhibited increased VAT AKR1C activity compared to those with the wildtype genotype. Analysis of blood lipid profile in the whole cohort revealed that "TT" carriers had elevated total cholesterol, low-density lipoprotein-cholesterol, and indices of insulin resistance. The rs28571858 SNP increased adipose tissue <i>AKR1C3</i> expression and activity in women. Increased AKR1C3 may contribute to an adipose tissue milieu that prompts lipogenesis, adversely affecting cardiometabolic health by disrupting lipid homeostasis and insulin sensitivity.<b>NEW & NOTEWORTHY</b> rs28571858 has a minor allele frequency of 18.7% in a cohort of 2,776 residents of Quebec, Canada. rs28571858 is associated with adipose tissue <i>AKR1C3</i> expression and activity in women. Minor allele homozygote carriers have increased total cholesterol, LDL-cholesterol, and indices of insulin resistance.