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*, Jan P. Tuckermann*

*Kontaktforfatter

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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.

OriginalsprogEngelsk
Artikelnummer2271
TidsskriftNature Communications
Vol/bind14
Antal sider16
ISSN2041-1723
DOI
StatusUdgivet - 20. apr. 2023

Bibliografisk note

Funding Information:
We acknowledge the University UIm animal caretakers and TFZ for their excellent work. G.C. is supported by ESFD/Lilly, Baustein Grant (University Clinic Ulm) ProtrainU grant (University Ulm) and Boehringer Ingelheim Travel Fonds grant. J.P.T. is supported by the Deutsche Forschungsgemeinschaft (CRC 1506 Aging at Interfaces, Project C05, Project Number 450627322). A.R. and A.J.M.J. are supported by a Lundbeck Fellowship (R335-2019-2195). We thank T. Chavakis (University Hospital Dresden) for critically reading the manuscript.

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