Sucnr1-KO Mouse

Sucnr1, also known as GPR91, belongs to the family of G protein-coupled receptors (GPCRs). It is activated by succinate, a citric acid cycle intermediate, triggering signaling pathways that indicate local stress affecting cellular metabolism. Sucnr1 has high potential as a drug target and is likely an important regulator of basic physiology [1].

Adipocyte-specific deletion of Sucnr1 influences metabolic health. It impairs leptin response to feeding, highlighting its role in nutrient-related leptin dynamics [2]. Myeloid-specific deficiency in Sucnr1 promotes a local pro-inflammatory phenotype and disrupts glucose homeostasis in mice, emphasizing its role in macrophage-mediated anti-inflammatory responses and metabolic regulation [3]. In β cells, mice with β cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, showing its importance in insulin secretion [5]. Sucnr1 deficiency in mice fed a choline-deficient high-fat diet led to both beneficial and detrimental effects on liver function, uncovering its role in hepatocyte glucose and lipid metabolism [4]. Also, succinate-induced renal injury in mice was found to be via Sucnr1-mediated tubular epithelial cell apoptosis [6].

In conclusion, Sucnr1 plays crucial roles in multiple biological processes such as energy metabolism, immune response, and insulin secretion. Gene knockout mouse models have been instrumental in revealing its functions in diseases like obesity-related metabolic disorders, non-alcoholic fatty liver disease, and kidney injury, providing insights into potential therapeutic targets for these conditions.

References:

1. Gilissen, Julie, Jouret, François, Pirotte, Bernard, Hanson, Julien. 2016. Insight into SUCNR1 (GPR91) structure and function. In Pharmacology & therapeutics, 159, 56-65. doi:10.1016/j.pharmthera.2016.01.008. https://pubmed.ncbi.nlm.nih.gov/26808164/

2. Villanueva-Carmona, Teresa, Cedó, Lídia, Madeira, Ana, Vendrell, Joan, Fernández-Veledo, Sonia. 2023. SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression. In Cell metabolism, 35, 601-619.e10. doi:10.1016/j.cmet.2023.03.004. https://pubmed.ncbi.nlm.nih.gov/36977414/

3. Keiran, Noelia, Ceperuelo-Mallafré, Victoria, Calvo, Enrique, Vendrell, Joan, Fernández-Veledo, Sonia. 2019. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. In Nature immunology, 20, 581-592. doi:10.1038/s41590-019-0372-7. https://pubmed.ncbi.nlm.nih.gov/30962591/

4. Marsal-Beltran, Anna, Rodríguez-Castellano, Adrià, Astiarraga, Brenno, Ceperuelo-Mallafré, Victòria, Fernández-Veledo, Sonia. 2023. Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD. In Metabolism: clinical and experimental, 145, 155630. doi:10.1016/j.metabol.2023.155630. https://pubmed.ncbi.nlm.nih.gov/37315889/

5. Sabadell-Basallote, Joan, Astiarraga, Brenno, Castaño, Carlos, Vendrell, Joan, Fernández-Veledo, Sonia. 2024. SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes. In The Journal of clinical investigation, 134, . doi:10.1172/JCI173214. https://pubmed.ncbi.nlm.nih.gov/38713514/

6. Pu, Min, Zhang, Jing, Zeng, Yongcheng, Gao, Guoquan, Zhou, Ti. 2023. Succinate-SUCNR1 induces renal tubular cell apoptosis. In American journal of physiology. Cell physiology, 324, C467-C476. doi:10.1152/ajpcell.00327.2022. https://pubmed.ncbi.nlm.nih.gov/36622070/