GPR171, a G protein-coupled receptor, has diverse functions. It has been linked to the regulation of food intake and metabolism as it is the receptor for the neuropeptide BigLEN [5]. It is also involved in pain modulation, T-cell immunity, and lipid metabolism, with its signaling pathways likely involving Gi/o-coupled mechanisms [4,3]. Genetic models, such as KO mouse models, have been crucial in understanding its functions.

In mice, GPR171 deficiency exacerbates DSS-and CD45RBhighCD4+ T cell-induced colitis, characterized by increased Th17 cell responses in the intestinal mucosa. Mechanistically, it promotes Th17 cell differentiation and lipid metabolism perturbation via the cAMP-pCREB-FABP5 axis [1]. In terms of pain, activation of GPR171 with an agonist attenuates morphine tolerance in both female and male mice on the tail-flick test, but not the hotplate test, and does not exacerbate morphine-induced tolerance and withdrawal during long-term morphine treatment [2]. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity [3].

In conclusion, GPR171 plays essential roles in intestinal inflammation, pain regulation, and T-cell immunity. The gene knockout mouse models have been instrumental in revealing its functions in these disease-related areas, such as in IBD treatment and pain management, offering potential therapeutic targets for these conditions.

References:

1. Kou, Fushun, Li, Xiao-Yu, Feng, Zhongsheng, Zhang, Qing, Liu, Zhanju. 2025. GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism. In Gut, , . doi:10.1136/gutjnl-2024-334010. https://pubmed.ncbi.nlm.nih.gov/40074327/

2. Afrose, Leela, McDermott, Max V, Bhuiyan, Ashif I, Pathak, Sanjai K, Bobeck, Erin N. 2022. GPR171 activation regulates morphine tolerance but not withdrawal in a test-dependent manner in mice. In Behavioural pharmacology, 33, 442-451. doi:10.1097/FBP.0000000000000692. https://pubmed.ncbi.nlm.nih.gov/35942845/

3. Fujiwara, Yuki, Torphy, Robert J, Sun, Yi, Schulick, Richard D, Zhu, Yuwen. 2021. The GPR171 pathway suppresses T cell activation and limits antitumor immunity. In Nature communications, 12, 5857. doi:10.1038/s41467-021-26135-9. https://pubmed.ncbi.nlm.nih.gov/34615877/

4. Cho, Pyung Sun, Lee, Han Kyu, Choi, Young In, Jung, Sung Jun, Hwang, Sun Wook. 2021. GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain. In Biomedicines, 9, . doi:10.3390/biomedicines9030256. https://pubmed.ncbi.nlm.nih.gov/33807709/

5. Gomes, Ivone, Aryal, Dipendra K, Wardman, Jonathan H, Fricker, Lloyd D, Devi, Lakshmi A. 2013. GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. In Proceedings of the National Academy of Sciences of the United States of America, 110, 16211-6. doi:10.1073/pnas.1312938110. https://pubmed.ncbi.nlm.nih.gov/24043826/