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.

• Authors: Fernanda Dana Mantelmacher, Isabel Zvibel, Keren Cohen, Alona Epshtein, Metsada Pasmanik-Chor, Thomas Vogl, Yael Kuperman, Shai Weiss, Daniel J Drucker, Chen Varol, Sigal Fishman
• Journal: Nature metabolism (Nat Metab) Vol. 1 Issue 1 Pg. 58-69 (01 2019) ISSN: 2522-5812 [Electronic] Germany
• PMID: 32694806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calgranulin A
• Calgranulin B
• Receptors, Gastrointestinal Hormone
• S100A8 protein, human
• S100A9 protein, human
• Gastric Inhibitory Polypeptide
• gastric inhibitory polypeptide receptor

Topics

• Animals
• Body Weight
• Bone Marrow (metabolism, pathology)
• Calgranulin A (genetics, metabolism)
• Calgranulin B (genetics, metabolism)
• Gastric Inhibitory Polypeptide (metabolism)
• Immunity
• Immunohistochemistry
• Inflammation (etiology, metabolism, pathology)
• Insulin Resistance (genetics)
• Mice
• Myeloid Cells (metabolism)
• Myelopoiesis (genetics)
• Phenotype
• Receptors, Gastrointestinal Hormone (deficiency, metabolism)