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Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

Author

Listed:
  • Giorgio Caratti

    (University of Ulm
    John Radcliffe Hospital
    University of Oxford)

  • Ulrich Stifel

    (University of Ulm)

  • Bozhena Caratti

    (University of Ulm)

  • Ali J. M. Jamil

    (Odense University Hospital
    University of Southern Denmark)

  • Kyoung-Jin Chung

    (University Hospital and Faculty of Medicine, Technical University Dresden)

  • Michael Kiehntopf

    (Jena University Hospital)

  • Markus H. Gräler

    (Jena University Hospital
    Jena University Hospital
    Jena University Hospital)

  • Matthias Blüher

    (University of Leipzig)

  • Alexander Rauch

    (Odense University Hospital
    University of Southern Denmark
    Steno Diabetes Center Odense)

  • Jan P. Tuckermann

    (University of Ulm)

Abstract

Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis. In contrast, GR deletion in Kupffer cells alone does not alter IR. Co-culture experiments show that the absence of GR in macrophages directly causes reduced phospho-AKT and glucose uptake in adipocytes, suggesting an important function of GR in ATM. GR-deficient macrophages are refractory to alternative ATM-inducing IL-4 signaling, due to reduced STAT6 chromatin loading and diminished anti-inflammatory enhancer activation. We demonstrate that GR has an important function in macrophages during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity.

Suggested Citation

  • Giorgio Caratti & Ulrich Stifel & Bozhena Caratti & Ali J. M. Jamil & Kyoung-Jin Chung & Michael Kiehntopf & Markus H. Gräler & Matthias Blüher & Alexander Rauch & Jan P. Tuckermann, 2023. "Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37831-z
    DOI: 10.1038/s41467-023-37831-z
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