The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages.
Julia S BrunnerAndrea VogelAlexander LercherMichael CalderaAna KorosecMarlene PühringerMelanie HofmannAlexander HajtoMarkus KielerLucia Quemada GarridoMartina KerndlMario KuttkeIldiko MesteriMaria Wiktoria GórnaMarta KulikPaulina Maria DominiakAmanda E BrandonEmma EstevezCasey L EganFlorian GruberMartina SchweigerJ Formula See Text Rg MencheAndreas BergthalerThomas WeichhartKristaps KlavinsMark A FebbraioOmar SharifGernot SchabbauerPublished in: Nature metabolism (2020)
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.
Keyphrases
- adipose tissue
- insulin resistance
- bone marrow
- cell proliferation
- high fat diet induced
- healthcare
- pi k akt
- metabolic syndrome
- public health
- type diabetes
- dendritic cells
- weight loss
- dna damage
- high fat diet
- mental health
- weight gain
- acute myeloid leukemia
- fatty acid
- dna repair
- mesenchymal stem cells
- health information
- poor prognosis
- immune response
- dna damage response
- health promotion
- body mass index
- long non coding rna
- human health