Ntsr2, belonging to the G protein-coupled receptor family like NTSR1, is a receptor for neurotensin (NTS). It has been implicated in multiple physiological and pathological processes, including analgesia, mental disorders, and cancers. It is particularly prevalent in the brain and may play specific roles in the nervous system [2].

In adipose tissue, adenoviral-mediated knockdown or knockout of NTS (produced by lymphatic endothelial cells) enhanced cold tolerance, an effect mediated by Ntsr2 and ERK signaling. Inhibition of Ntsr2 promoted energy expenditure and improved metabolic function in obese mice, suggesting its role in adipose thermogenesis [1]. In B-cell chronic lymphocytic leukemia (B-CLL), Ntsr2 was highly expressed and interacted with TrkB to protect B-CLL cells from apoptosis. Downregulation of Ntsr2 led to a decrease in cell viability via apoptotic cell death, indicating its potential as a therapeutic target in B-CLL [5]. In NTSR3/sortilin knockout mice, the expression of Ntsr2 was increased, leading to resistance to thermal and chemical pain, suggesting an interaction between Ntsr3/sortilin and Ntsr2 [3]. Also, Ntsr2-deficient mice showed reduced freezing response in contextual fear-conditioning tests, suggesting its role in fear memory [4]. Depletion of Ntsr2 in white adipocytes upregulated food intake, while local NTS treatment suppressed it, revealing its role in regulating food intake through ceramide metabolism [6].

In summary, Ntsr2 plays essential roles in adipose thermogenesis, pain response, fear memory, B-CLL cell survival, and food intake regulation. Gene knockout models, especially in mice, have been crucial in uncovering these functions, highlighting Ntsr2's potential as a therapeutic target in obesity-related metabolic disorders and B-CLL.

References:

1. Li, Jin, Li, Erwei, Czepielewski, Rafael S, Tsai, Linus, Rosen, Evan D. 2021. Neurotensin is an anti-thermogenic peptide produced by lymphatic endothelial cells. In Cell metabolism, 33, 1449-1465.e6. doi:10.1016/j.cmet.2021.04.019. https://pubmed.ncbi.nlm.nih.gov/34038712/

2. Yang, Yuting, Zhang, Wenxin, Wei, Kun, Ma, Yuan, Ouyang, Qing. . Physiological and Pathological Roles of NTSR2 in Several Organs and Diseases (Review). In Protein and peptide letters, 31, 3-10. doi:10.2174/0109298665267989231024064200. https://pubmed.ncbi.nlm.nih.gov/37962046/

3. Devader, Christelle, Moreno, Sébastien, Roulot, Morgane, Morales, Carlos R, Mazella, Jean. 2016. Increased Brain Neurotensin and NTSR2 Lead to Weak Nociception in NTSR3/Sortilin Knockout Mice. In Frontiers in neuroscience, 10, 542. doi:. https://pubmed.ncbi.nlm.nih.gov/27932946/

4. Yamauchi, Rena, Wada, Etsuko, Kamichi, Sari, Yamamoto, Tadashi, Wada, Keiji. . Neurotensin type 2 receptor is involved in fear memory in mice. In Journal of neurochemistry, 102, 1669-1676. doi:10.1111/j.1471-4159.2007.04805.x. https://pubmed.ncbi.nlm.nih.gov/17697051/

5. Abbaci, A, Talbot, H, Saada, S, Naves, T, Jauberteau, M O. 2017. Neurotensin receptor type 2 protects B-cell chronic lymphocytic leukemia cells from apoptosis. In Oncogene, 37, 756-767. doi:10.1038/onc.2017.365. https://pubmed.ncbi.nlm.nih.gov/29059151/

6. Fu, Wei, Lai, Yuanting, Li, Kexin, Huang, He, Li, Jin. 2025. Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism. In Cell research, 35, 117-131. doi:10.1038/s41422-024-01038-8. https://pubmed.ncbi.nlm.nih.gov/39748047/