Androgen Receptor is a Negative Regulator of PRDM16 in Beige Adipocyte

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.