Gcgr, the glucagon receptor, is a key player in glucose and lipid homeostasis, belonging to the class B1 G protein-coupled receptors [1,3]. It is involved in regulating energy metabolism, with glucagon binding to Gcgr triggering signaling pathways that impact glucose production and lipid metabolism [1]. Genetic models, such as KO/CKO mouse models, are valuable for studying Gcgr's functions.

Hepatocyte-specific deletion of Alkbh5 in mice reduces glucose and lipids by inhibiting the Gcgr and mTORC1 signaling pathways, highlighting Gcgr's role in metabolic regulation [1]. In addition, dual agonists of Gcgr/GLP-1R like BI 456906, cotadutide, and survodutide show potential in treating obesity, type 2 diabetes mellitus, and non-alcoholic steatohepatitis (NASH). For example, cotadutide's action on the liver to reduce lipid content, drive glycogen flux, and improve mitochondrial turnover is directly mediated through Gcgr signaling [2,4,5]. CD9 has been found to mediate the hepatic beneficial effects of Gcgr signaling, and its deficiency exacerbates diet-induced hepatic steatosis [6].

In conclusion, Gcgr is essential for maintaining glucose and lipid homeostasis. Gene-knockout mouse models have been instrumental in revealing its role in metabolic diseases, including obesity, type 2 diabetes, and NASH. Understanding Gcgr's functions provides potential therapeutic targets for these metabolic disorders [1,2,4,5,6].

References:

1. Ding, Kaixin, Zhang, Zhipeng, Han, Zhengbin, Chen, Xiao-Wei, Chen, Zheng. 2025. Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling. In Science (New York, N.Y.), 387, eadp4120. doi:10.1126/science.adp4120. https://pubmed.ncbi.nlm.nih.gov/40014709/

2. Zimmermann, Tina, Thomas, Leo, Baader-Pagler, Tamara, Neubauer, Heike, Augustin, Robert. 2022. BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. In Molecular metabolism, 66, 101633. doi:10.1016/j.molmet.2022.101633. https://pubmed.ncbi.nlm.nih.gov/36356832/

3. Li, Yang, Zhou, Qingtong, Dai, Antao, Wang, Ming-Wei, Cong, Zhaotong. 2023. Structural analysis of the dual agonism at GLP-1R and GCGR. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2303696120. doi:10.1073/pnas.2303696120. https://pubmed.ncbi.nlm.nih.gov/37549266/

4. Boland, Michelle L, Laker, Rhianna C, Mather, Karly, Trevaskis, James L, Rhodes, Christopher J. 2020. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. In Nature metabolism, 2, 413-431. doi:10.1038/s42255-020-0209-6. https://pubmed.ncbi.nlm.nih.gov/32478287/

5. Thomas, Leo, Martel, Eric, Rist, Wolfgang, Neubauer, Heike, Augustin, Robert. 2024. The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection. In Diabetes, obesity & metabolism, 26, 2368-2378. doi:10.1111/dom.15551. https://pubmed.ncbi.nlm.nih.gov/38560764/

6. Zheng, Yi, Wang, Yuren, Xiong, Xin, Qu, Hua, Zheng, Hongting. 2024. CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2400819. doi:10.1002/advs.202400819. https://pubmed.ncbi.nlm.nih.gov/38837628/