Intestinal interleukin (IL)-22Ra1 signaling mediates the onset of systemic metabolic disorders

Abstract

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.