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

Nature Metabolism
Fernanda Dana MantelmacherSigal Fishman

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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Citations

Aug 1, 2019·Cellular and Molecular Life Sciences : CMLS·Francesca RiuzziRosario Donato
Aug 28, 2020·Frontiers in Medicine·Xiaofan JiangXin Guo
Mar 11, 2021·Cell Reports·Daishi YamakawaMasaki Inagaki
Dec 9, 2020·Molecular Metabolism·Jonathan E Campbell
Jul 22, 2021·Nature Reviews. Immunology·Andrew J Murphy, Mark A Febbraio
Jul 27, 2021·Diabetes, Obesity & Metabolism·Michael A NauckAndreas F H Pfeiffer

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Methods Mentioned

BETA
ELISA
flow cytometry
PCA
Flow
enzyme-linked immunosorbent assay
PCR

Software Mentioned

TapeStation Analysis
FlowJo
Partek Genomics Suite
ingWAT
epiWAT
WebGestalt
Image J
DAVID
LabMaster
Accu

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