Gprc6a, a G-protein coupled receptor, is proposed to be a master regulator of complex endocrine networks and metabolic processes. It is activated by multiple ligands like osteocalcin, testosterone, basic amino acids, and various cations. Gprc6a is thought to integrate metabolic functions via coordinated hormone secretion and direct effects on glucose and fat metabolism in tissues such as the liver, skeletal muscle, and fat [1,2,3,4,5,6,7,8].

Genetic models, especially knockout (KO) mouse models, have been crucial in studying Gprc6a. Loss-of-Gprc6a in mice results in metabolic syndrome-like phenotypes, including obesity, glucose intolerance, hepatic steatosis, and insulin resistance [8]. Adipocyte-specific Gprc6a ablation promotes diet-induced obesity by inhibiting lipolysis [6]. Hepatocyte-specific conditional knockout (CKO) shows excessive hepatic fat accumulation and glycogen depletion, along with impaired glucose and pyruvate tolerance [7].

In conclusion, Gprc6a plays essential roles in metabolic regulation, including glucose and fat metabolism, as revealed by KO and CKO mouse models. These models contribute to understanding its role in metabolic syndrome, obesity, and related metabolic disorders, suggesting Gprc6a as a potential therapeutic target for these diseases [1,2,6,7,8].

References:

1. Pi, Min, Nishimoto, Satoru Kenneth, Quarles, L Darryl. 2016. GPRC6A: Jack of all metabolism (or master of none). In Molecular metabolism, 6, 185-193. doi:10.1016/j.molmet.2016.12.006. https://pubmed.ncbi.nlm.nih.gov/28180060/

2. Pi, Min, Nishimoto, Satoru Kenneth, Darryl Quarles, L. . Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling. In Endocrinology, 162, . doi:10.1210/endocr/bqab011. https://pubmed.ncbi.nlm.nih.gov/33474566/

3. Diaz-Franco, Martha Cristina, Franco-Diaz de Leon, Raul, Villafan-Bernal, Jose Rafael. 2018. Osteocalcin‑GPRC6A: An update of its clinical and biological multi‑organic interactions (Review). In Molecular medicine reports, 19, 15-22. doi:10.3892/mmr.2018.9627. https://pubmed.ncbi.nlm.nih.gov/30431093/

4. Jørgensen, Christinna V, Bräuner-Osborne, Hans. 2020. Pharmacology and physiological function of the orphan GPRC6A receptor. In Basic & clinical pharmacology & toxicology, 126 Suppl 6, 77-87. doi:10.1111/bcpt.13397. https://pubmed.ncbi.nlm.nih.gov/32056382/

5. He, Yumin, Su, Jingyun, Gao, Hongrui, Feng, Zemeng, Yin, Yulong. 2022. GPRC6A Mediates Glucose and Amino Acid Homeostasis in Mice. In Metabolites, 12, . doi:10.3390/metabo12080740. https://pubmed.ncbi.nlm.nih.gov/36005612/

6. Mukai, Satoru, Mizokami, Akiko, Otani, Takahito, Jimi, Eijiro, Hirata, Masato. 2021. Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis. In The Journal of biological chemistry, 296, 100274. doi:10.1016/j.jbc.2021.100274. https://pubmed.ncbi.nlm.nih.gov/33428938/

7. Pi, Min, Xu, Fuyi, Ye, Ruisong, Lu, Lu, Darryl Quarles, L. 2020. Role of GPRC6A in Regulating Hepatic Energy Metabolism in Mice. In Scientific reports, 10, 7216. doi:10.1038/s41598-020-64384-8. https://pubmed.ncbi.nlm.nih.gov/32350388/

8. Pi, Min, Quarles, L Darryl. 2012. Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. In Endocrinology, 153, 2062-9. doi:10.1210/en.2011-2117. https://pubmed.ncbi.nlm.nih.gov/22374969/