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  3. The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages

The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages

  • Nat Metab. 2020 Dec;2(12):1427-1442. doi: 10.1038/s42255-020-00311-5.
Julia S Brunner  # 1 2,  Andrea Vogel  # 1 2,  Alexander Lercher 3,  Michael Caldera 3 4,  Ana Korosec 5,  Marlene Pühringer 1 2,  Melanie Hofmann 1 2,  Alexander Hajto 1 2,  Markus Kieler 1 2,  Lucia Quemada Garrido 1 2,  Martina Kerndl 1 2,  Mario Kuttke 1 2,  Ildiko Mesteri 6,  Maria W Górna 7,  Marta Kulik 7,  Paulina M Dominiak 7,  Amanda E Brandon 8 9,  Emma Estevez 10,  Casey L Egan 10 11,  Florian Gruber 12,  Martina Schweiger 13,  Jörg Menche 3 4,  Andreas Bergthaler 3,  Thomas Weichhart 14,  Kristaps Klavins 3 15,  Mark A Febbraio 10 11,  Omar Sharif  # 16 17,  Gernot Schabbauer  # 18 19
Affiliations

Affiliations

  • 1 Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria.
  • 2 Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria.
  • 3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 4 Max Perutz Laboratories, Vienna, Austria.
  • 5 Skin and Endothelium Research Division, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
  • 6 Institute of Pathology Überlingen, Überlingen, Germany.
  • 7 Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Warsaw, Poland.
  • 8 Insulin Action and Energy Metabolism Laboratory, Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 9 Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.
  • 10 Cellular & Molecular Metabolism Laboratory, Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 11 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 12 Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
  • 13 Institute of Molecular Biosciences, University of Graz, Graz, Austria.
  • 14 Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
  • 15 Rudolfs Cimdins Riga Biomaterials Innovations and Development Centre, Riga Technical University, Riga, Latvia.
  • 16 Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria. omar.sharif@meduniwien.ac.at.
  • 17 Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. omar.sharif@meduniwien.ac.at.
  • 18 Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria. gernot.schabbauer@meduniwien.ac.at.
  • 19 Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. gernot.schabbauer@meduniwien.ac.at.
  • # Contributed equally.
PMID: 33199895 DOI: 10.1038/s42255-020-00311-5
Abstract

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.

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