Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

Giorgio Caratti, Ulrich Stifel, Bozhena Caratti, Ali J. M. Jamil, Kyoung-Jin Chung, Michael Kiehntopf, Markus H. Gräler, Matthias Blüher, Alexander Rauch () and Jan P. Tuckermann ()
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Giorgio Caratti: University of Ulm
Ulrich Stifel: University of Ulm
Bozhena Caratti: University of Ulm
Ali J. M. Jamil: Odense University Hospital
Kyoung-Jin Chung: University Hospital and Faculty of Medicine, Technical University Dresden
Michael Kiehntopf: Jena University Hospital
Markus H. Gräler: Jena University Hospital
Matthias Blüher: University of Leipzig
Alexander Rauch: Odense University Hospital
Jan P. Tuckermann: University of Ulm

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37831-z

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