Adipocyte-specific MC2R overexpression exerts minimal metabolic effects in mice

Abstract Background Obesity is often associated with elevated glucocorticoid (GC) levels mediated by melanocortin 2 receptor (MC2R), the adrenocorticotropic hormone (ACTH) receptor expressed in the adrenal gland. Meanwhile, previous in vitro studies in non-adrenal cells suggest a potential role for MC2R in lipid metabolism in murine primary adipocytes; however, the functional relevance of MC2R in vivo remains poorly understood. Here, we assessed the metabolic effects and therapeutic potential of MC2R in obesity and GC regulation in vivo by generating mice with adipocyte-specific MC2R overexpression using the adeno-associated virus doublef-floxed inverse orientation (AAV-DIO) system. Results Our findings show that under basal, high-fat diet (HFD), and stress-induced conditions, MC2R overexpression in adipocytes has minimal effects on thermogenic and lipolytic markers and is insufficient to promote weight reduction in mice. Moreover, adipocyte-specific overexpression of MC2R failed to sequester the ACTH and decrease elevated serum corticosterone levels after exogenous ACTH administration. Conclusions These findings demonstrate that adipocyte-specific MC2R overexpression does not induce strong metabolic benefits, suggesting that MC2R-directed gene therapy may not be an effective treatment strategy for obesity.