Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Nat Commun. 2020 Nov 18;11(1):5872. doi: 10.1038/s41467-020-19760-3.
Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease.
大量证据表明，代谢组织与免疫系统之间的串扰在肥胖的发生和发展中起作用。然而，对于中枢和外周代谢炎症的协调分子调控机制仍不完全清楚。在这里，我们鉴定出髓系 Krüppel 样因子 2（KLF2）是肥胖及其后果的一个重要调节因子。在小鼠和人类中，高脂肪饮食会下调髓系 KLF2 水平。在基础条件下，髓系特异性 KLF2 敲除小鼠（K2KO）表现出摄食量增加和体重增加。高脂肪饮食（HFD）喂养进一步加剧了 K2KO 的代谢疾病表型。从机制上讲，髓系 KLF2 的缺失会增加外周和中枢组织的代谢炎症。通过限食喂养、骨髓移植和小胶质细胞消融的组合实验，表明中枢和外周组织都对 K2KO 引起的代谢功能障碍有贡献。最后，髓系 KLF2 的过表达可保护小鼠免受 HFD 诱导的肥胖和胰岛素抵抗。综上所述，这些数据表明髓系 KLF2 是维持和疾病状态下中枢和外周代谢炎症的节点调节因子。
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