OR4M1, an olfactory G-protein-coupled receptor, is the cognate receptor of asprosin, a glucogenic and orexigenic hormone encoded by the FBN1 gene [3,4]. Asprosin binds to OR4M1 to activate the cAMP signaling circuitry, promoting hepatic glucose release and appetite stimulation [4]. OR4M1 thus plays a crucial role in energy metabolism and homeostasis. Genetic models, such as gene knockout mouse models, could potentially be used to further understand its functions.

In bovine granulosa cells, OR4M1 mRNA abundance was greater in small estrogen-inactive follicles compared to large or medium ones, indicating its developmental regulation in bovine follicles [1]. In ovarian cancer, OR4M1 is expressed in both normal and malignant human ovarian tissues, and its expression in liquid biopsies may have prognostic potential as asprosin seems to regulate numerous signaling pathways in-vitro [2,5]. In a high-fat diet/streptozotocin rat model of insulin resistance, citronellal alleviated insulin resistance by mitigating the Asprosin/OR4M1 signaling axis, with docking results showing citronellal blocked the Asprosin binding site at OR4M1 [7]. Also, in concussion-associated tauopathy, in-vitro activation of OR4M1 with a compound led to attenuation of abnormal tau phosphorylation, and in traumatic brain injury, OR4M1 was down-regulated in peripheral blood mononuclear cells, correlated with injury severity [6,8].

In conclusion, OR4M1 is essential in multiple biological processes. Through model-based research, it has been shown to be involved in ovarian follicular function, energy-related diseases like insulin resistance, and neurological conditions such as concussion-associated tauopathy and traumatic brain injury. These findings contribute to understanding the underlying mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Maylem, E R S, Spicer, L J, Batalha, I M, Schütz, L F. 2023. Developmental and hormonal regulation of FBN1 and OR4M1 mRNA in bovine granulosa cells. In Domestic animal endocrinology, 84-85, 106791. doi:10.1016/j.domaniend.2023.106791. https://pubmed.ncbi.nlm.nih.gov/37167929/

2. Kerslake, Rachel, Hall, Marcia, Vagnarelli, Paola, Kyrou, Ioannis, Karteris, Emmanouil. 2021. A pancancer overview of FBN1, asprosin and its cognate receptor OR4M1 with detailed expression profiling in ovarian cancer. In Oncology letters, 22, 650. doi:10.3892/ol.2021.12911. https://pubmed.ncbi.nlm.nih.gov/34386072/

3. Hoffmann, Jennifer G, Xie, Wei, Chopra, Atul R. . Energy Regulation Mechanism and Therapeutic Potential of Asprosin. In Diabetes, 69, 559-566. doi:10.2337/dbi19-0009. https://pubmed.ncbi.nlm.nih.gov/32198197/

4. Ovali, Mehmet Akif, Bozgeyik, Ibrahim. 2022. Asprosin, a C-Terminal Cleavage Product of Fibrillin 1 Encoded by the FBN1 Gene, in Health and Disease. In Molecular syndromology, 13, 175-183. doi:10.1159/000520333. https://pubmed.ncbi.nlm.nih.gov/35707591/

5. Kerslake, Rachel, Sisu, Cristina, Panfilov, Suzana, Kyrou, Ioannis, Karteris, Emmanouil. 2022. Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer. In Journal of clinical medicine, 11, . doi:10.3390/jcm11195942. https://pubmed.ncbi.nlm.nih.gov/36233808/

6. Zhao, Wei, Ho, Lap, Wang, Jun, Elder, Gregory A, Pasinetti, Giulio Maria. 2016. In Silico Modeling of Novel Drug Ligands for Treatment of Concussion Associated Tauopathy. In Journal of cellular biochemistry, 117, 2241-8. doi:10.1002/jcb.25521. https://pubmed.ncbi.nlm.nih.gov/26910498/

7. Abdelaziz, Aya, El-Far, Yousra M, Abdel-Rahman, Noha. 2025. Citronellal Alleviates Insulin Resistance in High-Fat Diet/Streptozocin Model: Role of Asprosin/Olfactory Receptor Axis. In Molecular nutrition & food research, 69, e202400654. doi:10.1002/mnfr.202400654. https://pubmed.ncbi.nlm.nih.gov/39821628/

8. Zhao, Wei, Ho, Lap, Varghese, Merina, Haroutunian, Vahram, Pasinetti, Giulio Maria. . Decreased level of olfactory receptors in blood cells following traumatic brain injury and potential association with tauopathy. In Journal of Alzheimer's disease : JAD, 34, 417-429. doi:10.3233/JAD-121894. https://pubmed.ncbi.nlm.nih.gov/23241557/