Gut hormone GIP facilitates APOE production by adipose tissue macrophages to support adipogenesis during obesity
2Department of Clinical Microbiology and Immunology, Faculty of Medical and Health Sciences, Tel-Aviv University
Obesity is a global epidemic. Under chronic energy surplus, visceral white adipose tissue (eWAT in mice) expands by an increase in adipocyte size (hypertrophy), leading to inflammation and insulin resistance. A healthier expansion mechanism relies on adipogenesis – the formation of new adipocytes from local adipocyte stem and progenitor cells (ASPC). Adipose tissue macrophages (ATMs) in eWAT are suggested to regulate adipogenesis by unclear mechanisms. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine cells upon nutrient ingestion to control glucose and energy balance. We have shown that depletion of GIP receptor (GIPR) in immune cells aggravates experimental obesity, leading to more significant weight gain, insulin resistance, hepatic steatosis, and impaired energy expenditure. However, GIP responding immune cells in epiWAT remained uknown. Utilizing GIPR-reporter mice, we characterized GIPR expression in eWAT ATM. BM chimeric mice, in which GIPR-deficiency is targeted to ATMs (Gipr-/- BM mice), exhibited increased eWAT mass and adipocyte hypertrophy after five weeks of HFD-induced obesity. This was accompanied by a reduced eWAT adipocyte number, impaired differentiation, and decreased ASPC numbers, leading to enhanced ectopic hepatic fat accumulation. Bulk RNA-seq analysis revealed in GIPR-deficient eWAT ATMs a significant downregulation of Apolipoprotein E (Apoe), which was further confirmed at the protein level. Treatment of HFD-fed WT mice with GIP analuoge increased its expression in eWAT ATM. Next, we applied the BM chimerism approach to target APOE deficiency in eWAT ATMs (Apoe-/- BM). Apoe-/- BM mice exhibited significant weight gain and enhanced eWAT hypertrophy. Collectively, our data uncovers a gut-WAT-immune axis governed by GIP, which conveys gut signals of excess energy to the buildup of new energy storage units - adipocytes, via its regulation of APOE expression in ATM.