Gcgr, the glucagon receptor, is a crucial protein involved in glucose and lipid homeostasis. It belongs to the class B1 G protein-coupled receptors and plays a key role in the glucagon signaling pathway. Activation of Gcgr has significant impacts on energy metabolism, influencing processes such as glycogenolysis, gluconeogenesis, and lipolysis, which are essential for maintaining normal blood glucose levels and energy balance [1,2,3,4,5,6,7]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying Gcgr's functions.

In a hepatocyte-specific Alkbh5 knockout mouse model, deletion of Alkbh5 reduces glucose and lipids by inhibiting the Gcgr signaling pathway, highlighting Gcgr's role in metabolic regulation [1]. Regarding anti-obesity research, dual agonists of Gcgr and GLP-1R like BI 456906, cotadutide, and survodutide have shown robust anti-obesity efficacy, reducing body weight through increased energy expenditure and decreased food intake, with Gcgr engagement contributing to the effects [2,3,5]. In non-alcoholic steatohepatitis (NASH) research, dual agonists of Gcgr/GLP-1R can reduce hepatic steatosis, fibrosis, and inflammation more effectively than GLP-1R agonists alone, suggesting Gcgr's potential in treating NASH [3,7]. Also, CD9 was found to mediate the hepatic beneficial effects of Gcgr agonists, with CD9 deficiency exacerbating diet-induced hepatic steatosis [6].

In conclusion, Gcgr is essential for maintaining glucose and lipid homeostasis. Research using KO/CKO mouse models has revealed its significance in metabolic diseases, obesity, and NASH. These findings suggest that targeting Gcgr, especially in combination with GLP-1R, could be a promising therapeutic strategy for treating metabolic disorders, obesity, and NASH.