Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Nat Commun. 2023 Apr 20;14(1):2271. doi: 10.1038/s41467-023-37831-z.
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.
肥胖时的胰岛素抵抗 (IR) 与脂肪组织巨噬细胞 (ATM) 驱动的脂肪组织炎症有关。生理水平的抗炎糖皮质激素 (GCs) 是否调节 IR 尚不清楚。在这里，我们报告说，在包括小鼠巨噬细胞在内的髓系细胞中敲除 GC 受体 (GR) 会由于抗炎性 ATM 减少而加剧肥胖相关的 IR，从而导致脂肪组织脂肪分解加剧和严重的肝脂肪变性。相比之下，单独敲除库普弗细胞中的 GR 不会改变 IR。共培养实验表明，巨噬细胞中 GR 的缺失直接导致脂肪细胞中磷酸化 AKT 和葡萄糖摄取减少，表明 GR 在 ATM 中具有重要功能。由于 STAT6 染色质加载减少和抗炎增强子激活减弱，缺乏 GR 的巨噬细胞对替代性 ATM 诱导的 IL-4 信号无反应。我们证明，GR 通过限制脂肪组织炎症和脂肪分解来促进胰岛素敏感性，在肥胖期间在巨噬细胞中具有重要功能。
