The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron–associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.
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We would like to thank the Unit for Imaging and Cytometry at the Instituto Gulbenkian de Ciência (IGC) for assistance with flow cytometry, cell sorting, and multiphoton microscopy. We also want to thank the Antibody Service at the IGC for the antibodies produced in house and the Histopathology facility at the IGC for tissue processing and histological assessment. This work was supported by the Fundação para a Ciéncia e Tecnologia (FCT), the European Molecular Biology Organization (EMBO), the Human Frontier Science Program (HFSP), Maratona da Saúde, and the US National Institutes of Health (NIH). R.M.P. was supported by FCT (SFRH/BD/88454/2012), J.S.S. was supported by the American Heart Association (16PRE30980030) and a training grant (T32DK007541), B.A.A. was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and N.M.-S. was supported by Xunta de Galicia (ED481B 2016/168-0). We thank M. Aouadi for helpful discussions.
The authors declare no competing financial interests.
Supplementary Figures 1–12 and Supplementary Table 1 (PDF 20527 kb)
Intra-vital multi-photon visualization of a neuro-adipose connection in the inguinal fat pad of a live Cx3cr1GFP/+ mouse; LipidTOX (blue) labels adipocytes. Images are representative of 3 similar experiments. (MPG 192 kb)
Intra-vital multi-photon visualization of the inguinal fat pad of a live Cx3cr1GFP/+ mouse; LipidTOX (blue) labels adipocytes. Images are representative of 3 similar experiments. (MPG 56 kb)
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Pirzgalska, R., Seixas, E., Seidman, J. et al. Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat Med 23, 1309–1318 (2017). https://doi.org/10.1038/nm.4422
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