Glucose dependent insulinotrophic polypeptide (GIP) immune cell interactions control body weight during obesity via modulation of energy expenditure

Incretin peptides, mainly glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are gut derived hormones, which are secreted upon cues from ingested food and regulate glucose concentration, eating behavior and energy expenditure to maintain body weight. As a result, a myriad of therapeutics for metabolic diseases based on the actions of incretins, particularly GLP-1, are currently under clinical use and development. Nevertheless, the biology of GIP in the immune system remains overlooked, plagued by contradictions and unanswered questions. Our lab has previously shown that the long-acting GIP analogue [d-Ala2]GIP reduces innate and adaptive inflammatory responses in the epidydimal adipose tissue (epiWAT) of high-fat diet (HFD) fed mice, but the direct immunometabolic roles of GIP remained unknown. Here, we show that mice with GIP receptor (GIPR)-deficiency targeted to immune cells display increased weight gain, insulin resistance, hepatic steatosis, myelopoiesis, impaired energy expenditure and impaired white adipose tissue (WAT) beiging under HFD. These effects were mediated by the unrestrained activity of the alarmin S100A8/A9 in GIPR-deficient myeloid immune cells. Recent studies have outlined a pivotal role for type 2 immune cell networks in maintaining metabolic homeostasis and energy balance. In alignment with their impaired energy expenditure, HFD fed mice with GIPR-deficiency in immune cells exhibited significant alterations in WAT type 2 inflammatory circuits, and co-deletion of S100A8/A9 was sufficient to restore it. Finally, GIP augmentation facilitated inguinal WAT beiging and induced the expression of the beiging supportive type 2 cytokines in lean mice under cold conditions. Collectively, our results identify an immune–GIPR–S100A8/A9 signaling axis coupling nutrient signals to the control of inflammation and adaptive thermogenesis.