Ffar1, also known as GPR40, is a G-protein-coupled receptor that functions as a receptor for medium-to long-chain free fatty acids [4,6]. It plays a crucial role in glucose-dependent insulin secretion and regulation of metabolism, and is thus a potential therapeutic target for type 2 diabetes mellitus (T2DM) [2,3,5,7]. It also controls T2DM through glucose-stimulated insulin secretion and incretin production [5]. Additionally, FFAR1 signaling may be involved in various physio-pathological processes, such as organ inflammation, fibrosis, and CNS disorders [1].

In FFAR1 gene-deficient mice, stronger inflammatory and peripheral neuropathic pain-like behavior as well as depressive-like behavior were observed. These findings suggest that FFAR1 may be involved in endogenous pain modulation, depressive-like behavior, and regulation of brain monoamine (dopamine and serotonin) releases, with FFAR1 indirectly regulating dopamine release by promoting serotonin release [4].

In conclusion, FFAR1 is essential for glucose-dependent insulin secretion and metabolic regulation. The study of FFAR1 gene-deficient mouse models has revealed its potential roles in pain modulation, emotional behaviors, and CNS-related disorders. These insights into FFAR1's functions provide a basis for exploring its potential as a therapeutic target in T2DM and other related diseases.

References:

1. Governa, Paolo, Caroleo, Maria Cristina, Carullo, Gabriele, Cione, Erika, Manetti, Fabrizio. 2021. FFAR1/GPR40: One target, different binding sites, many agonists, no drugs, but a continuous and unprofitable tug-of-war between ligand lipophilicity, activity, and toxicity. In Bioorganic & medicinal chemistry letters, 41, 127969. doi:10.1016/j.bmcl.2021.127969. https://pubmed.ncbi.nlm.nih.gov/33771587/

2. Li, Zheng, Zhou, Zongtao, Zhang, Luyong. 2019. Current status of GPR40/FFAR1 modulators in medicinal chemistry (2016-2019): a patent review. In Expert opinion on therapeutic patents, 30, 27-38. doi:10.1080/13543776.2020.1698546. https://pubmed.ncbi.nlm.nih.gov/31771391/

3. Ren, Qiang, Fan, Yiqing, Yang, Lixin, Shi, Wei, Qian, Hai. 2023. An updated patent review of GPR40/ FFAR1 modulators (2020 - present). In Expert opinion on therapeutic patents, 33, 565-577. doi:10.1080/13543776.2023.2272649. https://pubmed.ncbi.nlm.nih.gov/37947382/

4. Kurihara, Takashi. . [Possible involvement of FFAR1 signaling in mouse emotional behaviors through the regulation of brain monoamine releases]. In Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 158, 454-459. doi:10.1254/fpj.23054. https://pubmed.ncbi.nlm.nih.gov/37914322/

5. Paul, Abhik, Nahar, Sourin, Nahata, Pankaj, Karmakar, Sanmoy, Maity, Tapan Kumar. 2023. Synthetic GPR40/FFAR1 agonists: An exhaustive survey on the most recent chemical classes and their structure-activity relationships. In European journal of medicinal chemistry, 264, 115990. doi:10.1016/j.ejmech.2023.115990. https://pubmed.ncbi.nlm.nih.gov/38039791/

6. Kimura, Ikuo, Ichimura, Atsuhiko, Ohue-Kitano, Ryuji, Igarashi, Miki. 2019. Free Fatty Acid Receptors in Health and Disease. In Physiological reviews, 100, 171-210. doi:10.1152/physrev.00041.2018. https://pubmed.ncbi.nlm.nih.gov/31487233/

7. Li, Zheng, Xu, Xue, Huang, Wenlong, Qian, Hai. 2017. Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges. In Medicinal research reviews, 38, 381-425. doi:10.1002/med.21441. https://pubmed.ncbi.nlm.nih.gov/28328012/