NPFFR2, the neuropeptide FF receptor 2, is a G protein-coupled receptor (GPCR) [2]. It helps regulate pain, modulates the opioid system, and is involved in controlling energy balance, thermogenesis, and the function of the hypothalamic-pituitary-adrenal (HPA) axis [1,5,6]. It has been associated with pathways related to insulin signaling, RhoA/YAP signaling, and the regulation of neurotransmitter release [2,7,8].

In gene knockout (KO) mouse models, NPFFR2 deficiency leads to severe glucose intolerance, especially when fed a high-fat diet (HFD), along with reduced insulin pathway signaling proteins and the development of hypothalamic insulin resistance [1]. In male KO mice on HFD, there are lower body weights, white adipose tissues, liver weights, and plasma leptin levels, compensated by increased liver PPARα and plasma FGF21 [1]. In female KO mice, lipolysis in adipose tissue is inhibited due to attenuated Adra3β and Pparγ expression [1]. NPFFR2-KO mice also show resistance to LPS-induced depressive-like responses, stress-exposure-induced anxiety-like behaviors, and HPA axis hyperactivity [4,5]. In liver cancer, silencing of NPFFR2 reduces the malignancy of liver cancer cells [2]. Compound heterozygous variants of the NPFFR2 gene might be potentially associated with severe preeclampsia [3].

In conclusion, NPFFR2 plays crucial roles in metabolism, stress-related responses, pain regulation, and cancer malignancy. The KO mouse models have been instrumental in revealing its functions in conditions such as diabetes-related metabolic disorders, stress-anxiety disorders, and liver cancer, providing potential therapeutic targets for these diseases [1,2,3,4,5].

References:

1. Karnošová, Alena, Strnadová, Veronika, Železná, Blanka, Kašpárek, Petr, Maletínská, Lenka. . NPFFR2-deficient mice fed a high-fat diet develop strong intolerance to glucose. In Clinical science (London, England : 1979), 137, 847-862. doi:10.1042/CS20220880. https://pubmed.ncbi.nlm.nih.gov/37191311/

2. Shin, Yuna, Jung, Wonhee, Kim, Mi-Yeon, Kim, Sang-Bum, Shin, Hyun Jin. 2022. NPFFR2 Contributes to the Malignancy of Hepatocellular Carcinoma Development by Activating RhoA/YAP Signaling. In Cancers, 14, . doi:10.3390/cancers14235850. https://pubmed.ncbi.nlm.nih.gov/36497331/

3. Jiang, Huling, Wang, Luming, Zhu, Jianjun, Ping, Zepeng. 2022. NPFFR2 gene compound heterozygous variants associated with preeclampsia identified by whole-exome sequencing. In Gene, 854, 147108. doi:10.1016/j.gene.2022.147108. https://pubmed.ncbi.nlm.nih.gov/36535464/

4. Yu, Zachary, Lin, Ya-Tin, Chen, Jin-Chung. 2021. Knockout of NPFFR2 Prevents LPS-Induced Depressive-Like Responses in Mice. In International journal of molecular sciences, 22, . doi:10.3390/ijms22147611. https://pubmed.ncbi.nlm.nih.gov/34299230/

5. Lin, Ya-Tin, Huang, Yi-Ling, Tsai, Sze-Chi, Chen, Jin-Chung. 2020. Ablation of NPFFR2 in Mice Reduces Response to Single Prolonged Stress Model. In Cells, 9, . doi:10.3390/cells9112479. https://pubmed.ncbi.nlm.nih.gov/33202667/

6. Lin, Ya-Tin, Yu, Yu-Lian, Hong, Wei-Chen, Chen, Ting-Chun, Chen, Jin-Chung. 2017. NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents. In International journal of molecular sciences, 18, . doi:10.3390/ijms18081810. https://pubmed.ncbi.nlm.nih.gov/28825666/

7. Lin, Ya-Tin, Wu, Kuan-Hsuan, Jhang, Jie-Jhu, Hsu, Po-Hung, Li, Hui-Yun. 2024. Hypothalamic NPFFR2 attenuates central insulin signaling and its knockout diminishes metabolic dysfunction in mouse models of diabetes mellitus. In Clinical nutrition (Edinburgh, Scotland), 43, 603-619. doi:10.1016/j.clnu.2024.01.013. https://pubmed.ncbi.nlm.nih.gov/38301284/

8. Lin, Ya-Tin, Chen, Jin-Chung. 2018. Dorsal Root Ganglia Isolation and Primary Culture to Study Neurotransmitter Release. In Journal of visualized experiments : JoVE, , . doi:10.3791/57569. https://pubmed.ncbi.nlm.nih.gov/30346383/