The PI3K Pathway Preserves Metabolic Health through MARCO-dependent Lipid Uptake by Adipose Tissue Macrophages
Nature Metabolism
2020
Julia Stefanie Brunner,
Andrea Vogel,
Alexander Lercher,
Michael Caldera,
Ana Korošec,
Marlene Puehringer,
Melanie Hofman,
Alexander Hajto,
Markus Kieler,
Lucia Quemada Garrito,
Martina Kerndl,
Mario Kuttke,
Ildiko Mesteri,
Maria Wiktoria Gorno,
Marta Kulik,
Paulina Dominiak,
Amanda Elizabeth Brandon,
Emma Estevez,
Casey L. Egan,
Florian Gruber,
Martina Schweiger,
Joerg Menche,
Andreas Bergthaler,
Thomas Weichhart,
Kristaps Kļaviņš,
Mark A Febbraio,
Omar Sharif,
Gernot Schabbauer
Adipose tissue macrophages (ATMs) display tremendous heterogeneity depending on signals in their local microenvironment and contribute to the pathogenesis of obesity. The phosphoinositide 3-kinase (PI3K) signalling pathway, antagonized by the phosphatase and tensin homologue (PTEN), is important for metabolic responses to obesity. We hypothesized that fluctuations in macrophage-intrinsic PI3K activity via PTEN could alter the trajectory of metabolic disease by driving distinct ATM populations. Using mice harbouring macrophage-specific PTEN deletion or bone marrow chimeras carrying additional PTEN copies, we demonstrate that sustained PI3K activity in macrophages preserves metabolic health in obesity by preventing lipotoxicity. Myeloid PI3K signalling promotes a beneficial ATM population characterized by lipid uptake, catabolism and high expression of the scavenger macrophage receptor with collagenous structure (MARCO). Dual MARCO and myeloid PTEN deficiencies prevent the generation of lipid-buffering ATMs, reversing the beneficial actions of elevated myeloid PI3K activity in metabolic disease. Thus, macrophage-intrinsic PI3K signalling boosts metabolic health by driving ATM programmes associated with MARCO-dependent lipid uptake.
Keywords
Adipose tissue macrophages, metabolism, lipids, PI3K pathway
DOI
10.1038/s42255-020-00311-5
Hyperlink
https://www.nature.com/articles/s42255-020-00311-5
Brunner, J., Vogel, A., Lercher, A., Caldera, M., Korošec, A., Puehringer, M., Hofman, M., Hajto, A., Kieler, M., Garrito, L., Kerndl, M., Kuttke, M., Mesteri, I., Gorno, M., Kulik, M., Dominiak, P., Brandon, A., Estevez, E., Egan, C., Gruber, F., Schweiger, M., Menche, J., Bergthaler, A., Weichhart, T., Kļaviņš, K., Febbraio, M., Sharif, O., Schabbauer, G. The PI3K Pathway Preserves Metabolic Health through MARCO-dependent Lipid Uptake by Adipose Tissue Macrophages. Nature Metabolism, 2020, Vol. 2, No. 12, pp.1427-1442. ISSN 2522-5812. Available from: doi:10.1038/s42255-020-00311-5
Publication language
English (en)