Adipocyte IL-22RA1 signaling promotes structural and functional remodeling of white adipose tissue following acute intestinal damage.

Interleukin (IL)-22 has been shown to play an important role in intestinal host defense and ameliorating high-fat diet (HFD)-induced metabolic disorders primarily through signaling in intestinal epithelial cells. Adipocytes have emerged as key immune-metabolic regulators that influence intestinal inflammation in inflammatory bowel disease (IBD). However, the role of IL-22RA1 signaling in adipocytes has not been explored. In the present study, we examined the role of IL-22RA1 signaling in adipocytes in response to dextran sulfate sodium (DSS)-mediated gut inflammation. To do this, we subjected adipocyte specific Il22ra1 knockout mice (Il22ra1Adipo) to intestinal inflammation under normal chow and HFD conditions. Compared to littermate controls, Il22ra1Adipo mice displayed significant weight loss on day 9 of DSS treatment and showed altered expression of immune response- and lipid metabolism-related genes in white adipose tissue (WAT) under a normal chow diet. Notably, when mice were primed with HFD prior to DSS-induced intestinal injury, WAT from Il22ra1Adipo mice showed a significant reduction in Fabp4 expression and a marked increase in the proliferation marker Ki67. These findings indicate that loss of IL-22RA1 signaling in adipocytes disrupts adipocyte differentiation and lipid metabolism, leading to increased proliferation of preadipocytes or stromal cells without proper maturation. Importantly, this altered adipose tissue response occurred despite similar levels of colonic inflammation between knockout and control mice, suggesting a critical role for adipocyte IL-22RA1 signaling in maintaining metabolic and inflammatory homeostasis in WAT during combined metabolic and intestinal inflammatory stress.