GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9

Abstract

Enteroendocrine cells relay energy-derived signals to immune cells to signal states of nutrient abundance and control immunometabolism. Emerging data suggest that the gut-derived nutrient-induced incretin glucose-dependent insulinotropic polypeptide (GIP) operates at the interface of metabolism and inflammation. Here we show that high-fat diet (HFD)-fed mice with immune cell-targeted GIP receptor (GIPR) deficiency exhibit greater weight gain, insulin resistance, hepatic steatosis and significant myelopoiesis concomitantly with impaired energy expenditure and inguinal white adipose tissue (WAT) beiging. Expression of the S100 calcium-binding protein S100A8 was increased in the WAT of mice with immune cell-targeted GIPR deficiency and co-deletion of GIPR and the heterodimer S100A8/A9 in immune cells ameliorated the aggravated metabolic and inflammatory phenotype following a HFD. Specific GIPR deletion in myeloid cells identified this lineage as the target of GIP effects. Furthermore, GIP directly downregulated S100A8 expression in adipose tissue macrophages. Collectively, our results identify a myeloid–GIPR–S100A8/A9 signalling axis coupling nutrient signals to the control of inflammation and adaptive thermogenesis.

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Fig. 1: Gipr −/− BM mice display increased weight gain and insulin resistance.
Fig. 2: epiWAT of Gipr −/− BM mice shows increased expression of S100A8 and myelopoiesis.
Fig. 3: Gipr −/− BM mice exhibit attenuated energy expenditure.
Fig. 4: Double deletion of GIPR and S100A8/A9 from immune cells reverses the metabolic phenotype displayed by Gipr −/− BM mice.
Fig. 5: Combined deletion of GIPR and S100A8/A9 from immune cells reverses the myelopoiesis phenotype of Gipr −/− BM mice.
Fig. 6: GIP negatively regulates S100A8 expression in myeloid cells.

Data availability

The microarray datasets generated during the current study are deposited at the National Center for Biotechnology Information Gene Expression Omnibus public database under accession code GSE109371.

Change history

  • 01 March 2019

    In the version of the article originally published, Fig. 3a was missing a y-axis line and key labels, and Fig. 3c,d had illegible text labels overlapping the graphs. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors acknowledge support from the Israel Science Foundation for C.V. and S.F. (grant nos 35/12 and 1146/16) and the Canada Research Chairs Program and Canadian Institutes of Health Research Foundation grant 154321, both to D.J.D. Y.K. is the incumbent of the Sarah and Rolando Uziel Research Associate Chair. We thank A. H. Futerman and Y. Pewzner-Jung for their assistance with metabolic cages experiments. Finally, we thank N. Strauss (Sourasky Medical Center) for radiation services.

Author information

F.D.M., I.Z., C.V. and S.F. conceived the study, designed experiments and wrote the manuscript. F.D.M., I.Z and C.V. performed the experiments and analysed the data. M.P-C. performed the bioinformatic analyses. T.V. analysed data, provided reagents and reviewed the manuscript. K.C., A.E. and S.W. performed many of the RT–PCR and immunoblot analyses in the presented experiments. Y.K. greatly assisted in the performance of metabolic cages experiments and analyses. D.J.D. provided key scientific consultation, essential reagents and mouse tools and carefully reviewed and edited the manuscript.

Correspondence to Sigal Fishman.

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Mantelmacher, F.D., Zvibel, I., Cohen, K. et al. GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nat Metab 1, 58–69 (2019). https://doi.org/10.1038/s42255-018-0001-z

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