Physiological fatty acid uptake reveals spatial and systemic constraints on nutrient accessibility in vivo

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Immune cells rely on exogenous fatty acids (FA) for membrane synthesis, bioenergetics and signalling, yet current approaches cannot accurately quantify physiological FA uptake in vivo. Here, we use cyclopropene-tagged fatty acids (cpFA) that, unlike existing FA-uptake tools, are taken up by physiologically relevant mechanisms. We measure FA uptake at single-cell resolution in vivo and uncover a previously unappreciated distinction between nutrient uptake capacity and nutrient accessibility. Although arachidonic acid exhibits the highest uptake capacity ex vivo across immune populations, it displays limited tissue accessibility in vivo, whereas palmitate is broadly accessible. In vivo nutrient-uptake measurements reveal that tissue architecture shapes nutrient accessibility, with spatial constraints in the spleen and exclusion of circulating FA, but not amino acids, from the thymus. Together, these findings identify nutrient accessibility as a distinct layer of metabolic regulation and reveal that immune-cell metabolism is shaped by spatial and systemic constraints on nutrient access Highlights Nutrient accessibility is a distinct layer of metabolic regulation Physiological FA uptake differs from ex vivo uptake capacity Spatial and systemic factors govern fatty-acid accessibility Tissue context shapes immune-cell metabolism in vivo In brief Using bioorthogonal FA to quantify physiological nutrient uptake in vivo, Wang et al. show that nutrient accessibility is distinct from nutrient uptake capacity. Tissue architecture and systemic FA distribution create spatial constraints on nutrient access, revealing an underappreciated layer of metabolic regulation in immune cells.

Authors 15

1. Xinyuan Wang

   Trinity College Dublin

   Affiliation as printed

   School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin, Ireland

2. Graham A. Heieis Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center for Infectious Disease, Albinusdreef 2, Leiden, The Netherlands,

3. Connor Corrigan

   Trinity College Dublin

   Affiliation as printed

   School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin, Ireland

4. Chang Liu

   Met Éireann

   Affiliation as printed

   Climate Services Division, Met Éireann, Dublin, D09 Y921, Ireland

5. Luuk Reinalda Aachen Department of Chemical Biology and Immunology Leiden Institute of Chemistry

   Leiden University

   Affiliation as printed

   Department of Chemical Biology and Immunology, Leiden Institute of Chemistry, Einsteinweg 33, Leiden, The Netherlands

6. Laura I. Bogue Aachen Department of Chemical Biology and Immunology Leiden Institute of Chemistry

   Leiden University

   Affiliation as printed

   Department of Chemical Biology and Immunology, Leiden Institute of Chemistry, Einsteinweg 33, Leiden, The Netherlands

7. Kas Steuten Aachen Department of Chemical Biology and Immunology Leiden Institute of Chemistry

   Leiden University

   Affiliation as printed

   Department of Chemical Biology and Immunology, Leiden Institute of Chemistry, Einsteinweg 33, Leiden, The Netherlands

8. Kristine Bertheussen Aachen Department of Chemical Biology and Immunology Leiden Institute of Chemistry

   Leiden University

   Affiliation as printed

   Department of Chemical Biology and Immunology, Leiden Institute of Chemistry, Einsteinweg 33, Leiden, The Netherlands

9. Marouane el Boujadayni
10. Jeroen M Punt Aachen Department of Molecular Physiology Leiden Institute of Chemistry

    Leiden University

    Affiliation as printed

    Department of Molecular Physiology, Leiden Institute of Chemistry, Einsteinweg 33, Leiden, The Netherlands

11. Linda V. Sinclair

    University of Dundee

    Affiliation as printed

    Division of Cell Signalling and Immunology, Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom

12. Mario van der Stelt Aachen Department of Chemical Biology and Immunology Leiden Institute of Chemistry

    Leiden University

    Affiliation as printed

    Department of Chemical Biology and Immunology, Leiden Institute of Chemistry, Einsteinweg 33, Leiden, The Netherlands

13. Bart Everts Aachen

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center for Infectious Disease, Albinusdreef 2, Leiden, The Netherlands,

14. Sander I. van Kasteren Aachen Department of Chemical Biology and Immunology Leiden Institute of Chemistry

    Leiden University

    Affiliation as printed

    Department of Chemical Biology and Immunology, Leiden Institute of Chemistry, Einsteinweg 33, Leiden, The Netherlands

15. David K. Finlay

    Trinity College Dublin

    Affiliation as printed

    School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin, Ireland

    School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin, Ireland