Neurotensin is an anti-thermogenic peptide produced by lymphatic endothelial cells

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

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.

Cell Metab. 2021 Jul 6;33(7):1449-1465.e6. doi: 10.1016/j.cmet.2021.04.019. Epub 2021 May 25.