Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine

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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.

Author information

Author notes

    • Roksana M Pirzgalska
    •  & Elsa Seixas

    These authors contributed equally to this work.


  1. The Howard Hughes Medical Institute (HHMI) and Obesity Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.

    • Roksana M Pirzgalska
    • , Elsa Seixas
    • , Noelia Martínez Sánchez
    • , Inês Mahú
    • , Raquel Mendes
    • , Vitka Gres
    • , Nadiya Kubasova
    • , Imogen Morris
    • , Bernardo A Arús
    • , Chelsea M Larabee
    • , Miguel Vasques
    • , Sathyavathy Anandan
    •  & Ana I Domingos
  2. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.

    • Jason S Seidman
    • , Verena M Link
    • , Nathanael J Spann
    •  & Christopher K Glass
  3. Faculty of Biology, Department II, Ludwig-Maximilians Universität München, Planegg-Martinsried, Germany.

    • Verena M Link
  4. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

    • Bernardo A Arús
  5. Department of Endocrinology, Curry Cabral Hospital, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

    • Miguel Vasques
  6. Department of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, EPE, Lisbon, Portugal.

    • Francisco Tortosa
  7. Electron Microscopy Unit, Instituto Gulbenkian de Ciência, Oeiras, Portugal.

    • Ana L Sousa
    •  & Erin Tranfield
  8. Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Maureen K Hahn
  9. Division of Immunology, Transplantation and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.

    • Matteo Iannacone
  10. The Howard Hughes Medical Institute (HHMI), New York, New York, USA.

    • Ana I Domingos


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A.I.D. conceptualized the study. R.M.P. performed two-photon and confocal microscopy. E.S. and R.M.P. performed flow cytometry. J.S.S. and R.M.P. performed low-input RNA-seq. V.M.L., J.S.S., and R.M.P. analyzed the RNA-seq data. M.I., A.L.S., S.A., and E.T. performed electron microscopy. E.S., R.M.P., N.M.S., I. Mahú, B.A.A., and C.M.L. performed functional tests. N.K., I. Morris, R.M., and V.G. performed related mouse husbandry and genotyping. F.T. and M.V. processed human ganglia. M.K.H. provided the Slc6a2−/− mice. N.J.S. developed the low-input RNA-seq protocols. A.I.D., C.K.G., and R.M.P. wrote the original draft of the manuscript. A.I.D., C.K.G., R.M.P., and C.M.L. reviewed and edited the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ana I Domingos.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12 and Supplementary Table 1

  2. 2.

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  1. 1.

    In vivo visualization of SAMs in the neuro-adipose connection.

    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.

  2. 2.

    In vivo visualization of ATMs in the subcutaneous adipose tissue

    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.