The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages.
Adipocytes
/ pathology
Adipose Tissue
/ metabolism
Animals
Bone Marrow Transplantation
Cell Differentiation
Chimera
Glucose Tolerance Test
Lipid Metabolism
/ genetics
Lipidomics
Macrophages
/ metabolism
Metabolic Diseases
/ metabolism
Mice
Mice, Inbred C57BL
Obesity
/ metabolism
PTEN Phosphohydrolase
/ genetics
Phosphatidylinositol 3-Kinases
/ genetics
Receptors, Immunologic
/ genetics
Signal Transduction
/ genetics
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
02
01
2020
accepted:
09
10
2020
pubmed:
18
11
2020
medline:
6
1
2021
entrez:
17
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33199895
doi: 10.1038/s42255-020-00311-5
pii: 10.1038/s42255-020-00311-5
doi:
Substances chimiques
Marco protein, mouse
0
Receptors, Immunologic
0
PTEN Phosphohydrolase
EC 3.1.3.67
Pten protein, mouse
EC 3.1.3.67
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1427-1442Subventions
Organisme : Austrian Science Fund FWF
ID : P 30026
Pays : Austria
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 677006
Pays : International
Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
ID : 31568
Pays : International
Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
ID : 31106
Pays : International
Organisme : Österreichischen Akademie der Wissenschaften (Austrian Academy of Sciences)
ID : DOC
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : APP1116936
Pays : International
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