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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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.
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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.
The authors declare no competing interests.
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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
- GIP Receptor (GIPR)
- S100A4 Expression
- Uncoupling Protein (UCP1)
Cellular and Molecular Life Sciences (2020)