Sucnr1-KO Mouse

Sucnr1, also known as GPR91, belongs to the family of G protein-coupled receptors (GPCRs). It has been paired with succinate, a citric acid cycle intermediate, and is involved in indicating local stress that may impact cellular metabolism. Succinate triggers Sucnr1-related signaling pathways, which are potentially linked to multiple physiological and pathophysiological processes [1].

Adipocyte-specific deletion of Sucnr1 influences leptin response to feeding, highlighting its role in controlling energy metabolism by modulating the circadian clock and leptin expression [2]. Myeloid-specific deficiency in Sucnr1 promotes a local pro-inflammatory phenotype, disrupts glucose homeostasis, exacerbates diet-induced obesity, and impairs adipose-tissue browning [3]. In hepatocytes, Sucnr1 deficiency leads to both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis, inflammation, and reduced glycogen content) effects in the liver, and disrupts glucose homeostasis [4]. Mice with β cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet [5]. Succinate-induced renal injury is mediated by Sucnr1 activation, causing tubular epithelial cell apoptosis [6]. SUCNR1-deficient mice fail to improve the intestinal barrier function and metabolic phenotype in high-fat diet-fed mice [7].

In summary, Sucnr1 plays essential roles in energy metabolism, immune response, inflammation regulation, and metabolism-related disease processes. The use of gene knockout (KO) and conditional knockout (CKO) mouse models has been crucial in revealing its functions in adipocytes, macrophages, hepatocytes, pancreatic β cells, renal tubular cells, and intestinal epithelial cells, providing insights into its potential as a therapeutic target for diseases such as obesity, diabetes, non-alcoholic fatty liver disease, and kidney damage.

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/

7. Li, Xuan, Huang, Guowen, Zhang, Yanan, Zhu, Weiyun, Yu, Kaifan. 2023. Succinate signaling attenuates high-fat diet-induced metabolic disturbance and intestinal barrier dysfunction. In Pharmacological research, 194, 106865. doi:10.1016/j.phrs.2023.106865. https://pubmed.ncbi.nlm.nih.gov/37482326/