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Liver macrophages regulate systemic metabolism through non-inflammatory factors

Abstract

Liver macrophages (LMs) have been proposed to contribute to metabolic disease through secretion of inflammatory cytokines. However, anti-inflammatory drugs lead to only modest improvements in systemic metabolism. Here we show that LMs do not undergo a proinflammatory phenotypic switch in obesity-induced insulin resistance in flies, mice and humans. Instead, we find that LMs produce non-inflammatory factors, such as insulin-like growth factor–binding protein 7 (IGFBP7), that directly regulate liver metabolism. IGFBP7 binds to the insulin receptor and induces lipogenesis and gluconeogenesis via activation of extracellular-signal-regulated kinase (ERK) signalling. We further show that IGFBP7 is subject to RNA editing at a higher frequency in insulin-resistant than in insulin-sensitive obese patients (90% versus 30%, respectively), resulting in an IGFBP7 isoform with potentially higher capacity to bind to the insulin receptor. Our study demonstrates that LMs can contribute to insulin resistance independently of their inflammatory status and indicates that non-inflammatory factors produced by macrophages might represent new drug targets for the treatment of metabolic diseases.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request. Custom codes used for GSEA are available upon request. All sequence data for this study have been deposited in the Sequence Read Archive (SRA) under accession numbers PRJNA483744 (mouse data) and PRJNA491664 (human data).

Change history

  • 04 April 2019

    In the version of this article initially published, author Volker M. Lauschke had affiliation number 13; the correct affiliation number is 12. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We are grateful to R. Harris, S. Craige and B. Craige for their considerable input on the manuscript. We thank T. Dolezal and M. Jindra for helpful suggestions on the Drosophila work. We also thank T. Schröder and R. Kuiper for the tissue histology, M. Taipale and J. Liu for performing sequencing, and A. Krstic for providing flow cytometry support. We thank M. Nordstrand for organising the collection of human obese liver biopsies. This work was supported by research grants from AstraZeneca through the ICMC (M.A.), the Swedish Research Council (M.A.; 2015-03582), the Stockholm County Council (E.N.), the Novo Nordisk Foundation, including the Tripartite Immuno-metabolism Consortium (M.A. and TrIC; NNF15CC0018486), the Strategic Research Program in Diabetes at Karolinska Institutet (M.A. and E.N.), the Diabetes Wellness Foundation Sweden (J.J.) and the Ruth and Richard Julin Foundation (C.M.).

Author information

C.M. carried out most experiments. G.K. and A.B. performed and analysed the data from the Drosophila experiments. J.J., L.L., V.A., E.B., A.S., C.X., M.T., C.K. and F.V. helped with experiments and interpretation of the data. S.S. measured circulating lipid levels in mice. A.T. measured lipids in Drosophila. K.H. generated all electron microscopy images and measurements. N.K.B. and E.E. provided biopsies and liver cells from lean individuals. E.N. provided liver biopsies from obese human subjects. M.R. provided serum from obese and lean volunteers. T.H. and V.M.L. performed experiments in human liver spheroids. X.L. and C.K. performed the bioinformatics analysis and interpretation. J.B. contributed to the design of experiments related to IGFBP7 signalling. C.M. and M.A. conceived the project, analysed data and wrote the manuscript with input from all co-authors.

Correspondence to Myriam Aouadi.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Figures 1–8 and Supplementary Tables 1–8

Reporting Summary

Supplementary Data 1

Significantly regulated pathways in human LMs isolated from obese as compared to lean patients. GSEA depicting significantly up- or downregulated pathways (FDR < 0.05) in human LMs according to MES.

Supplementary Data 2

Significantly regulated pathways in LMs isolated from HFD-fed mice as compared to ND-fed mice. GSEA depicting significantly up- or downregulated pathways (FDR < 0.05) in mouse LMs according to MES.

Supplementary Data 3

Obesity-regulated genes in mouse LMs and in mouse whole liver. List of regulated genes in LMs and in whole liver from mice fed a HFD as compared to mice fed a ND. Data include gene name, log2 fold change (log2FC), P value and FDR.

Supplementary Data 4

Highly expressed and upregulated genes in LMs isolated from HFD-fed mice as compared to ND-fed mice. List of upregulated genes in LMs isolated from HFD-fed as compared to ND-fed mice with median RPKM > 50. Data include gene name, log2 fold change (log2FC), P value and FDR.

Supplementary Data 5

Gene expression regulated by obesity and insulin resistance in human LMs. List of regulated genes in LMs isolated from humans: obese as compared to lean patients and obese insulin-resistant as compared to obese insulin-sensitive patients. Data include gene name, log2 fold change (log2FC), P value and FDR.

Supplementary Data 6

Gene expression regulated in mouse LMs following Igfbp7 silencing. List of regulated genes in LMs isolated from mice treated with GeRP-Scr versus GeRP-Igfbp7. Data includes gene name, log2 fold change (log2FC), P value and FDR.

Supplementary Data 7

Gene ontology enrichment analysis of inversely regulated genes in LMs from HFD- versus ND-fed mice and mice treated with GeRP-Igfbp7 versus GeRP-Scr. Complete list of inversely regulated pathways in mice fed a HFD versus ND as compared to mice treated with GeRP-Igfbp7 versus GeRP-Scr.

Supplementary Data 8

Genes regulated in mouse hepatocytes following Igfbp7 silencing in LMs. List of regulated genes in hepatocytes isolated from mice treated with GeRP-Scr versus GeRP-Igfbp7. Data include gene name, log2 fold change (log2FC), P value and FDR.

Supplementary Data 9

Significantly regulated pathways in mouse hepatocytes following Igfbp7 silencing in LMs. GSEA depicting significantly up- or downregulated pathways (FDR < 0.05) in human and mouse LMs according to MES.

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Further reading

Fig. 1: Obesity-induced insulin resistance occurs independently of inflammation.
Fig. 2: High-fat feeding increases Igfbp7 expression in LMs.
Fig. 3: Phenotype of Igfbp7-deficient LMs.
Fig. 4: Silencing of Igfbp7 in LMs decreases hyperglycaemia and hepatic steatosis.
Fig. 5: LM-derived IGFBP7 increases lipogenesis and gluconeogenesis.
Fig. 6: Proposed models for IGFBP7 signalling in mice and humans.