Neurotensin is an Anti-thermogenic Peptide Produced by Lymphatic Endothelial Cells

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2021 May 26

PMID 34038712

Citations 24

Authors

Jin Li

Erwei Li

Rafael S Czepielewski

Jingyi Chi

Xiao Guo

Yong-Hyun Han

Daqing Wang

Luhong Wang

Bo Hu

Brian Dawes

Christopher Jacobs

Danielle Tenen

Samuel J Lin

Bernard Lee

Donald Morris

Adam Tobias

Gwendalyn J Randolph

Paul Cohen

Linus Tsai

Evan D Rosen

Affiliations

Soon will be listed here.

Abstract

The lymphatic vasculature plays important roles in the physiology of the organs in which it resides, though a clear mechanistic understanding of how this crosstalk is mediated is lacking. Here, we performed single-cell transcriptional profiling of human and mouse adipose tissue and found that lymphatic endothelial cells highly express neurotensin (NTS/Nts). Nts expression is reduced by cold and norepinephrine in an α-adrenergic-dependent manner, suggesting a role in adipose thermogenesis. Indeed, NTS treatment of brown adipose tissue explants reduced expression of thermogenic genes. Furthermore, adenoviral-mediated overexpression and knockdown or knockout of NTS in vivo reduced and enhanced cold tolerance, respectively, an effect that is mediated by NTSR2 and ERK signaling. Inhibition of NTSR2 promoted energy expenditure and improved metabolic function in obese mice. These data establish a link between adipose tissue lymphatics and adipocytes with potential therapeutic implications.

Citing Articles

Neurotensin via Type I Receptor Modulates the Endotoxemia Induced Oxido-Inflammatory Stress on the Sympathetic Adrenomedullary System of Mice Regulating NF-κβ/Nor-Epinephrine Pathway.

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PMID: 39881060 DOI: 10.1007/s12013-025-01679-5.

WTAP regulates postnatal development of brown adipose tissue by stabilizing METTL3 in mice.

Wang Y, Li X, Liu C, Zhou L, Shi L, Zhang Z Life Metab. 2025; 1(3):270-284.

PMID: 39872074 PMC: 11749075. DOI: 10.1093/lifemeta/loac028.

Neurotensin signaling in fat modulates food intake.

Jang Y, Rajbhandari P Cell Res. 2025; 35(2):85-86.

PMID: 39748048 PMC: 11770060. DOI: 10.1038/s41422-024-01048-6.

Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism.

Fu W, Lai Y, Li K, Yang Y, Guo X, Gong Q Cell Res. 2025; 35(2):117-131.

PMID: 39748047 PMC: 11770130. DOI: 10.1038/s41422-024-01038-8.

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.

Yang M, Ge J, Liu Y, Wang H, Wang Z, Li D Nat Commun. 2024; 15(1):7746.

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References

Russell J, Zimmerman K, Middendorf W . Evidence for alpha-adrenergic innervation of the isolated canine thoracic duct. J Appl Physiol Respir Environ Exerc Physiol. 1980; 49(6):1010-5. DOI: 10.1152/jappl.1980.49.6.1010. View

Kabashima K, Shiraishi N, Sugita K, Mori T, Onoue A, Kobayashi M . CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am J Pathol. 2007; 171(4):1249-57. PMC: 1988874. DOI: 10.2353/ajpath.2007.070225. View

Zhao Q, Eichten A, Parveen A, Adler C, Huang Y, Wang W . Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment. Cancer Res. 2018; 78(9):2370-2382. DOI: 10.1158/0008-5472.CAN-17-2728. View

Wang J, Li N, Li H, Cui L, Wang P . Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1. Neuropeptides. 2011; 45(2):151-6. DOI: 10.1016/j.npep.2011.01.002. View

McGeown J, McHale N, Thornbury K . The effect of electrical stimulation of the sympathetic chain on peripheral lymph flow in the anaesthetized sheep. J Physiol. 1987; 393:123-33. PMC: 1192384. DOI: 10.1113/jphysiol.1987.sp016814. View

Vanlandewijck M, He L, Mae M, Andrae J, Ando K, Del Gaudio F . A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018; 554(7693):475-480. DOI: 10.1038/nature25739. View

Rosen E . The molecular control of adipogenesis, with special reference to lymphatic pathology. Ann N Y Acad Sci. 2003; 979:143-58; discussion 188-96. DOI: 10.1111/j.1749-6632.2002.tb04875.x. View

Zhang F, Zarkada G, Han J, Li J, Dubrac A, Ola R . Lacteal junction zippering protects against diet-induced obesity. Science. 2018; 361(6402):599-603. PMC: 6317738. DOI: 10.1126/science.aap9331. View

Ratner C, Skov L, Raida Z, Bachler T, Bellmann-Sickert K, Le Foll C . Effects of Peripheral Neurotensin on Appetite Regulation and Its Role in Gastric Bypass Surgery. Endocrinology. 2016; 157(9):3482-92. DOI: 10.1210/en.2016-1329. View

10.

Chen W, Xia P, Wang H, Tu J, Liang X, Zhang X . The endothelial tip-stalk cell selection and shuffling during angiogenesis. J Cell Commun Signal. 2019; 13(3):291-301. PMC: 6732145. DOI: 10.1007/s12079-019-00511-z. View

11.

Randolph G, Ivanov S, Zinselmeyer B, Scallan J . The Lymphatic System: Integral Roles in Immunity. Annu Rev Immunol. 2016; 35:31-52. PMC: 5551392. DOI: 10.1146/annurev-immunol-041015-055354. View

12.

Dupouy S, Viardot-Foucault V, Alifano M, Souaze F, Plu-Bureau G, Chaouat M . The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression. PLoS One. 2009; 4(1):e4223. PMC: 2626627. DOI: 10.1371/journal.pone.0004223. View

13.

Macosko E, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M . Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015; 161(5):1202-1214. PMC: 4481139. DOI: 10.1016/j.cell.2015.05.002. View

14.

Zeng W, Pirzgalska R, Pereira M, Kubasova N, Barateiro A, Seixas E . Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell. 2015; 163(1):84-94. PMC: 7617198. DOI: 10.1016/j.cell.2015.08.055. View

15.

Johnson L, Jackson D . The chemokine CX3CL1 promotes trafficking of dendritic cells through inflamed lymphatics. J Cell Sci. 2013; 126(Pt 22):5259-70. PMC: 3828594. DOI: 10.1242/jcs.135343. View

16.

Rutkowski J, Markhus C, Gyenge C, Alitalo K, Wiig H, Swartz M . Dermal collagen and lipid deposition correlate with tissue swelling and hydraulic conductivity in murine primary lymphedema. Am J Pathol. 2010; 176(3):1122-9. PMC: 2832135. DOI: 10.2353/ajpath.2010.090733. View

17.

Kleczkowska P, Lipkowski A . Neurotensin and neurotensin receptors: characteristic, structure-activity relationship and pain modulation--a review. Eur J Pharmacol. 2013; 716(1-3):54-60. DOI: 10.1016/j.ejphar.2013.03.004. View

18.

Richard F, Barroso S, Martinez J, Labbe-Jullie C, Kitabgi P . Agonism, inverse agonism, and neutral antagonism at the constitutively active human neurotensin receptor 2. Mol Pharmacol. 2001; 60(6):1392-8. DOI: 10.1124/mol.60.6.1392. View

19.

Chi J, Wu Z, Choi C, Nguyen L, Tegegne S, Ackerman S . Three-Dimensional Adipose Tissue Imaging Reveals Regional Variation in Beige Fat Biogenesis and PRDM16-Dependent Sympathetic Neurite Density. Cell Metab. 2018; 27(1):226-236.e3. DOI: 10.1016/j.cmet.2017.12.011. View

20.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View