Previous studies indicate that IL-17A plays an important role in mediating the intestinal microbiota and systemic metabolic functions. However, it is not known where IL-17RA signaling occurs to mediate these effects. To investigate this question, we used intestinal epithelial–specific (Il17raΔIEC) and liver-specific (Il17raΔLiver) IL-17RA knockout mice as well as littermate control mice. Our results indicate that intestinal IL-17RA signaling helps mediate systemic metabolic functions upon exposure to prolonged high-fat diet. Il17raΔIEC mice display impaired glucose metabolism, altered hormone and adipokine levels, increased visceral adiposity, and greater hepatic lipid deposition when compared with their littermate controls. We show that IL-17RA–driven changes in microbiota composition are responsible for regulating systemic glucose metabolism. Altogether, our data elucidate the importance of intestinal IL-17RA signaling in regulating high-fat diet–mediated systemic glucose and lipid metabolism.

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.

Interleukin (IL)-22 has been shown to protect against detrimental high fat diet (HFD)-induced phenotypes. However, it is unknown where IL-22Ra1 signaling specifically occurs to regulate HFD-induced metabolic disorders. To examine this, we utilized intestinal epithelium-specific Il22Ra1fl/fl;Villin-cre+ (IL22Ra1ΔIEC), white adipose tissue (WAT)-specific Il22Ra1fl/fl;Adipoq-cre+ (IL22Ra1ΔWAT), and liver-specific Il22Ra1fl/fl;Albumin-cre+ (IL22Ra1ΔLiver) knockout mice as well as their respective littermate cre-(IL22Ra1fl/fl), mice. When placed on long term HFD, IL22Ra1ΔIECand IL22Ra1ΔLiver mice but not IL22Ra1ΔWAT mice displayed impaired systemic glucose metabolism. We specifically observed that impaired glucose metabolism of IL22Ra1ΔIEC mice was microbiota dependent. IL22Ra1ΔIEC mice also possessed altered lipid metabolism since their intestinal tissues expressed increased levels of peroxisomal β-oxidation genes. Furthermore, extra-intestinal tissues from IL22Ra1ΔIEC mice displayed altered metabolism. Liver tissue of IL22Ra1ΔIEC mice displayed decreased expression of G6PC, a key glycolytic enzyme, and WAT displayed increased expression of peroxisomal Acox1 and decreased levels of certain fatty acids. These liver- and WAT-specific changes were dependent on IL-22 since Il22−/− mice displayed opposite trends in gene expression. We decided to examine where intestinal IL-22Ra1 signaling may specifically occur to mediate these effects. Interestingly, we observed a unique role of Paneth cell-specific IL-22Ra1 signaling in mediating systemic glucose metabolism. Overall, our data highlight a specific importance of intestinal IL-22Ra1 signaling in regulating HFD-induced metabolic disorders.