Gcgr, the glucagon receptor, is a key player in glucose homeostasis and energy metabolism [1,2,3,4,5,6,7,8]. It is involved in pathways such as the regulation of blood glucose levels, with glucagon binding to Gcgr triggering a series of intracellular events. Gcgr is also associated with lipid metabolism. Genetic models, especially knockout (KO) or conditional knockout (CKO) mouse models, have been instrumental in studying its functions [1].

In hepatocyte-specific Alkbh5 knockout mice, inhibition of Gcgr led to reduced glucose and lipids, indicating its role in maintaining glucose and lipid homeostasis [1]. In another study, GLP-1R/ Gcgr dual-agonist Cotadutide showed that Gcgr signaling directly mediated actions in the liver, such as reducing lipid content, driving glycogen flux, and improving mitochondrial function [4]. These KO/CKO mouse models provide insights into the role of Gcgr in metabolic diseases like type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD) [1,4].

In conclusion, Gcgr is essential for regulating glucose and lipid homeostasis. Studies using Gcgr KO/CKO mouse models have revealed its significance in metabolic diseases, offering potential therapeutic targets for conditions such as T2DM and MAFLD [1,4].

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/

7. Monfeuga, Thomas, Norlin, Jenny, Bugge, Anne, Feigh, Michael, Holst, Dorte. 2023. Evaluation of long acting GLP1R/GCGR agonist in a DIO and biopsy-confirmed mouse model of NASH suggest a beneficial role of GLP-1/glucagon agonism in NASH patients. In Molecular metabolism, 79, 101850. doi:10.1016/j.molmet.2023.101850. https://pubmed.ncbi.nlm.nih.gov/38065435/

8. Singh, Anmol, Sohal, Aalam, Batta, Akash. . GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis. In World journal of gastroenterology, 30, 5205-5211. doi:10.3748/wjg.v30.i48.5205. https://pubmed.ncbi.nlm.nih.gov/39735270/