ADGRL4 induces adipose browning and weight loss via AKT activation

Brown and beige adipose tissues, which contain high levels of mitochondria and UCP1, are crucial for energy expenditure and metabolic homeostasis. Previous studies have established that G protein-coupled receptors (GPCRs) play a critical role in mediating adaptive thermogenesis and browning. While the β3-adrenoceptor (β3-AR) serves as the key β-adrenergic GPCR driving adipose thermogenesis in mice, its minimal presence in human adipocytes hinders its therapeutic application. This study identifies adhesion G protein-coupled receptor L4 (ADGRL4) as a potential GPCR target for inducing adipose browning. In vitro experiments demonstrated that ADGRL4 activation promotes beige adipocyte differentiation, significantly upregulates UCP1 expression, and reduces lipid droplet accumulation. In vivo, ADGRL4 activation induces the development of beige fat in mice fed a normal chow diet without causing systemic effects. In mice fed a high-fat diet, ADGRL4 activation reduces fat deposition, decreases body weight, alleviates glucose intolerance, and ameliorated obesity and associated metabolic dysfunction. Furthermore, mechanistic investigations revealed that ADGRL4 specifically enhances AKT phosphorylation without altering total AKT levels, thereby activating a downstream signaling cascade that elevates UCP1 expression. This coordinated regulation through the p-AKT/UCP1 axis substantiates the role of ADGRL4 in driving adipose browning and identifies it as a promising molecular target for the treatment of obesity and associated metabolic disorders.