Constitutively active receptor ADGRA3 signaling induces adipose thermogenesis

The induction of adipose thermogenesis plays a critical role in maintaining body temperature and improving metabolic homeostasis to combat obesity. β3-adrenoceptor (β3-AR) is widely recognized as a canonical β-adrenergic G protein-coupled receptor (GPCR) that plays a crucial role in mediating adipose thermogenesis in mice. Nonetheless, the limited expression of β3-AR in human adipocytes restricts its clinical application. The objective of this study was to identify a GPCR that is highly expressed in human adipocytes and to explore its potential involvement in adipose thermogenesis. Our research findings have demonstrated that the adhesion G protein-coupled receptor A3 (ADGRA3), an orphan GPCR, plays a significant role in adipose thermogenesis through its constitutively active effects. ADGRA3 exhibited high expression levels in human adipocytes and mouse brown fat. Furthermore, the knockdown ofAdgra3resulted in an exacerbated obese phenotype and a reduction in the expression of thermogenic markers. Conversely,Adgra3overexpression activated the adipose thermogenic program and improved metabolic homeostasis without an exogenous ligand supplementation. We found that ADGRA3 facilitates the biogenesis of beige adipocytes through the Gs-PKA-CREB axis. Moreover, hesperetin was identified as a potential agonist of ADGRA3, capable of inducing adipocyte browning and ameliorating insulin resistance. In conclusion, our study demonstrated that the overexpression of constitutively active ADGRA3 or the activation of ADGRA3 by hesperetin can induce adipocyte browning by Gs-PKA-CREB axis. These findings indicate that the utilization of hesperetin and the selectively overexpression of ADGRA3 in adipose tissue could serve as promising therapeutic strategies in the fight against obesity.