Androgen Receptor is a Negative Regulator of PRDM16 in Beige Adipocyte.
Androgen Receptor is a Negative Regulator of PRDM16 in Beige Adipocyte.
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DOI：
10.1002/advs.202300070
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发表时间：
2023-07
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PRDM16（含PR结构域蛋白16）是棕色和米色脂肪细胞的显性激活因子。然而，调控PRDM16表达的机制尚不完全清楚。建立了Prdm16荧光素酶敲入报告基因小鼠模型，实现了对Prdm16转录的高通量监测。单克隆分析显示，Prdm16在腹股沟白色脂肪组织（iWAT）细胞中的表达具有高度异质性。在所有转录因子中，雄激素受体（Ar）与Prdm16负相关最强。PRDM16 mRNA的性别二态性表达在人类WAT中存在，女性个体的表达高于男性。雄激素- AR信号动员抑制Prdm16的表达，同时在米色脂肪细胞中减弱，而在棕色脂肪组织中则没有。雄激素对北京的抑制作用在Prdm16过表达时被消除。靶标切割和标记定位显示，AR在Prdm16基因座的内含子区域内直接结合，而Ucp1和其他褐变相关基因未被检测到直接结合。脂肪细胞选择性缺失Ar增强了米色细胞的生物发生，而脂肪细胞特异性过表达Ar则减弱了白色脂肪的形成。本研究强调了AR在WAT中负调控PRDM16的重要作用，并为观察到的脂肪含量性别差异提供了解释。利用PRDM16报告因子模型，雄激素受体（AR）被鉴定为PRDM16最强的负调控因子，在人和小鼠中均表现出性别二态表达。雄激素- AR复合物结合在Prdm16的内含子区域，从而抑制其表达并减轻脂肪褐变。这项研究为脂肪褐变的性别差异提供了一种新的解释。
PRDM16 (PR domain containing protein 16) serves as a dominant activator of brown and beige adipocyte. However, mechanisms underlying the regulation of PRDM16 expression are incompletely understood. A Prdm16 luciferase knockin reporter mouse model is generated, enabling high throughput monitoring of Prdm16 transcription. Single clonal analysis reveals high heterogeneity of Prdm16 expression in the inguinal white adipose tissue (iWAT) cells. Amongst all transcription factors, androgen receptor (Ar) shows the strongest negative correlation with Prdm16. A sex dimorphism for PRDM16 mRNA expression is present in human WAT, with female individuals exhibiting increased expression than males. Androgen‐AR signaling mobilization suppresses Prdm16 expression, accompanied by attenuated beiging in beige adipocytes, but not in brown adipose tissue. The suppressive effect of androgens on beiging is abolished upon overexpression of Prdm16. Cleavage under targets and tagmentation mapping reveals direct binding of AR within the intronic region of Prdm16 locus, whereas no direct binding is detected on Ucp1 and other browning‐related genes. Adipocyte‐selective deletion of Ar potentiates beige cell biogenesis whereas adipocyte‐specific overexpression of AR attenuates white adipose beiging. This study highlights an essential role of AR in negative regulation of PRDM16 in WAT and provides an explanation for the observed sex difference in adipose beiging. Utilizing a PRDM16 reporter model, androgen receptor (AR) is identified as the strongest negative regulator of PRDM16, which displays a sex dimorphic expression in both human and mouse. Androgen‐AR complex binds at the intronic region of Prdm16, and thereby suppresses its expression and mitigates adipose browning. The study provides a new explanation for sex‐difference in adipose browning.
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