Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec-Université Laval, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, Québec, Canada; École de Nutrition, Université Laval, 2425 Rue de l'Agriculture, G1V 0A6, Québec City, Québec, Canada.
Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
Mol Cell Endocrinol. 2021 May 1;527:111220. doi: 10.1016/j.mce.2021.111220. Epub 2021 Mar 3.
Changes in androgen dynamics within adipose tissue have been proposed as modulators of body fat accumulation. In this context, AKR1C2 likely plays a significant role by inactivating 5α-dihydrotestosterone.
To characterize AKR1C2 expression patterns across adipose depots and cell populations and to provide insight into the link with body fat distribution and genetic regulation.
We used RNA sequencing data from severely obese patients to assess patterns of AKR1C2 and AKR1C3 expression in abdominal adipose tissue depots and cell fractions. We additionally used data from 856 women to assess AKR1C2 heritability and to link its expression in adipose tissue with body fat distribution. Further, we used public resources to study AKR1C2 genetic regulation as well as reference epigenome data for regulatory element profiling and functional interpretation of genetic data.
We found that mature adipocytes and adipocyte-committed adipocyte progenitor cells (APCs) had enriched expression of AKR1C2. We found adipose tissue AKR1C2 and AKR1C3 expression to be significantly and positively associated with percentage trunk fat mass in women. We identified strong genetic regulation of AKR1C2 by rs28571848 and rs34477787 located on the binding sites of two nuclear transcription factors, namely retinoid acid-related orphan receptor alpha and the glucocorticoid receptor.
We confirm the link between AKR1C2, adipogenic differentiation and adipose tissue distribution. We provide insight into genetic regulation of AKR1C2 by identifying regulatory variants mapping to binding sites for the glucocorticoid receptor and retinoid acid-related orphan receptor alpha which may in part mediate the effect of AKR1C2 expression on body fat distribution.
脂肪组织中雄激素动态的变化被认为是调节体脂肪积累的因素。在这种情况下，AKR1C2 通过使 5α-二氢睾酮失活可能发挥重要作用。
描述 AKR1C2 在脂肪组织中的表达模式及其与体脂分布和遗传调控的关系。
我们使用来自严重肥胖患者的 RNA 测序数据来评估腹部脂肪组织和细胞亚群中 AKR1C2 和 AKR1C3 的表达模式。我们还使用了 856 名女性的数据来评估 AKR1C2 的遗传率，并将其在脂肪组织中的表达与体脂分布联系起来。此外，我们使用公共资源来研究 AKR1C2 的遗传调控，并利用参考表观基因组数据进行调控元件分析和对遗传数据的功能解释。
我们发现成熟脂肪细胞和脂肪细胞定向的脂肪细胞祖细胞（APCs）中 AKR1C2 的表达丰富。我们发现脂肪组织 AKR1C2 和 AKR1C3 的表达与女性躯干脂肪质量百分比呈显著正相关。我们发现 rs28571848 和 rs34477787 强烈调节 AKR1C2 的表达，这两个位点位于两个核转录因子的结合位点上，即视黄酸相关孤儿受体α和糖皮质激素受体。
我们证实了 AKR1C2、成脂分化和脂肪组织分布之间的联系。通过确定位于糖皮质激素受体和视黄酸相关孤儿受体α结合位点的调节变异，我们深入了解了 AKR1C2 的遗传调控，这些调节变异可能部分介导了 AKR1C2 表达对体脂分布的影响。
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