Npffr2, short for neuropeptide FF receptor 2, is a G protein-coupled receptor (GPCR) that helps regulate pain, modulates the opioid system, and is involved in controlling energy balance and thermogenesis [1,2,7]. It participates in pathways such as the hypothalamic-pituitary-adrenocortical (HPA) axis and may influence insulin-related energy homeostasis [4,5,6]. Genetic models, like knockout mice, are valuable for studying its functions.

In Npffr2-deficient male and female mice, there is severe glucose intolerance, especially when fed a high-fat diet. HFD-fed Npffr2 KO male mice have lower body weights, white adipose tissues, liver, and plasma leptin levels. Npffr2 deletion also prevents LPS-induced depressive-like responses and reduces the response to single prolonged stress in mice. In addition, Npffr2 activation leads to hyperalgesia through up-regulating the pain mediator CGRP [1,3,4,7].

In conclusion, Npffr2 plays a crucial role in multiple biological processes including metabolism, stress-related responses, and pain regulation. The study of Npffr2 KO mouse models has provided insights into its functions in diseases such as diabetes-related metabolic disorders, depression-like behaviors, and post-traumatic stress disorder-like conditions [1,3,4,6].

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. 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/

4. 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/

5. 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/

6. 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/

7. Lin, Ya-Tin, Liu, Ho-Ling, Day, Yuan-Ji, Hsu, Po-Hung, Chen, Jin-Chung. 2017. Activation of NPFFR2 leads to hyperalgesia through the spinal inflammatory mediator CGRP in mice. In Experimental neurology, 291, 62-73. doi:10.1016/j.expneurol.2017.02.003. https://pubmed.ncbi.nlm.nih.gov/28179153/