Intestinal Interleukin (IL)-22RA1 signaling regulates the reciprocal control of IL-22 and onset of high fat diet-induced metabolic disorders

Abstract

Abstract Impaired signaling by IL-22 has been shown to accelerate high fat diet (HFD)-induced obesity. However, it is not known if IL-22 signaling in the intestine regulates HFD-induced metabolic disorders. To test this, intestinal epithelial-specific IL-22RA1 knockout mice – Il22RA1fl/fl;Villin cre+ (IL-22RA1ΔIEC) and control Il22RA1fl/fl;Villin cre- (IL-22RA1fl/fl) mice – were generated. When placed on HFD for 16 weeks, IL- 22RA1ΔIEC and IL-22RA1fl/fl mice display commensal dysbiosis, reduced antimicrobial peptide expression, and dysregulated IL-22 responses. No difference in weight gain was observed between these mice over the 16-week period. Interestingly, IL-22RA1ΔIEC mice displayed decreased glucose tolerance when compared to controls. Upon antibiotic treatment, differences in glucose tolerance between these mice were not observed. Furthermore, this difference in glucose tolerance was not due to histopathology changes in white adipose tissue (WAT) or liver tissue. In IL-22RA1ΔIEC mice, we observed that expression of genes related to β-oxidation (Acox1) were increased in the WAT, and liver tissues displayed decreased expression of β-oxidation (Pparα) and glycolysis (G6PC) genes. These changes were not observed in Il22−/− mice or liver-specific IL-22RA1 knockout mice which suggests IL-22 may drive the expression of critical metabolic genes in the WAT and liver. We found exacerbated IL-22 response in HFD-fed IL-22RA1ΔIEC mice. Indeed, injection of IL-22RA1ΔIEC mice with anti-IL-22 decreased glucose tolerance when compared to IL-22RA1ΔIEC mice injected with an isotype control. Collectively, our data suggest that IL-22 signaling in the intestinal epithelium is important for regulating HFD-induced metabolic disorder.