Macrophage deletion of Noc4l triggers endosomal TLR4/TRIF signal and leads to insulin resistance

Yongli Qin,Sławomir Wołczyński,Xinmin Ren,Yuanwu Liu,Haiwen Li,Xiangdong Li,Jiyan Zhang,Nafis Rahman ,Wenqiang Ma,Dangsheng Li,Haifeng Li,Mei Liu,Lina Jia,Jinghua Yan,Xiru Li,Hua You,Shuoqian Ma,Pingping Li,Yan Guo,Huijiao Liu,Yang‐Dong Guo ,Fazheng Ren,Adam Krętowski

doi:10.1038/s41467-021-26408-3

Abstract

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The ribosome biosynthesis protein NOC4 (NOC4) mediates 40 S ribosomal subunits synthesis in yeast. Hereby, we reported an unexpected location and function of NOC4L, which was preferentially expressed in human and mouse macrophages. NOC4L was decreased in both obese human and mice. The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. Conversely, Noc4l overexpression by lentivirus treatment and transgenic mouse model improved glucose metabolism in mice. Importantly, we found that Noc4l can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorated LSI and IR in mice.

Highlights

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR)
We reported an unexpected location and function of Nucleolar complex associated 4 homolog (NOC4L) in macrophages, demonstrated that NOC4L was decreased in obese subjects and mice
By using the Lv-Noc4l, macrophage-specific deletion and overexpression of Noc4l mouse models, and several studies in vitro, we clarified a previously unidentified biological function of NOC4L, which directly interacted with TLR4 to inhibit its endocytosis and blocked the TRIF pathway

Summary

Introduction

Macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. A growing number of studies suggest that in obesity, there is an increased accumulation of proinflammatory macrophages in insulin target tissues, including adipose[3], muscle[4], and liver[5], driving low-grade chronic systemic inflammation (LSI)[6,7]. We found that NOC4L expression was decreased in both obese subjects and mice. By using lentivirusNoc4l (Lv-Noc4l), myeloid-specific deletion, and overexpression of Noc4l transgenic mouse models, as well as experiments in vitro, we clarified an unexpected function of NOC4L, in inhibiting TLR4 internalization and the TLR4/TRIF pathway in endosomes of macrophages involved in LSI and IR. We further found that overexpression of Noc4l can prevent LSI and IR induced by high-fat diet (HFD)

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Results

Conclusion