GIP receptor regulates adipose tissue inflammation and whole body metabolism through direct regulation of S100A8 in immune cells

Enteroendocrine cells relay energy-derived signals to immune cells to signal states of nutrient abundance and control immunometabolism. Emerging data suggest that the glucose-dependent insulinotropic polypeptide (GIP), a gut-derived nutrient-induced incretin, operates at the interface of metabolism and inflammation. Nevertheless, multiple studies in different models have yielded controversial results concerning the role of GIP in the control of body weight and inflammation. Some studies have found anti-obesogenic and anti-inflammatory GIP effects, while others have shown the opposite. In our recent study, 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. S100A8 protein expression was increased in the WAT of mice with immune cell-targeted GIPR-deficiency. Of note, direct administration of S100A8/A9 (calprotectin), significantly reduced beiging in inguinal fat of mice challenged with cold conditions. Importantly, co-deletion of GIPR and S100A8/A9 in immune cells ameliorated the aggravated metabolic and inflammatory phenotype following HFD. The myeloid lineage was identified as the specific target of GIP responsible for these effects. Equally, GIP directly down-regulated S100A8 expression in adipose tissue macrophages. Collectively, our results identify a myeloid-GIPR-S100A8/A9 signaling axis coupling nutrient signals to the control of inflammation and adaptive thermogenesis. The results of the presence study may bear therapeutics implication enlightening GIPR as a target to pharmaceutical intervention