Interleukin‐19 Regulates Adipose Tissue Dysfunction in Obesity: Interplay Between Inflammation and Vascularization

ABSTRACT Expanding visceral white adipose tissue (WAT) becomes hypoxic due to lack of compensatory vascularization. Hypoxia initiates inflammation, presumably to promote angiogenesis. Unfortunately, in obesity this results in adipocyte dysfunction and related cardiometabolic complications due to chronic low‐grade inflammation. We hypothesize that IL‐19 acts as a vascular and immunometabolic protective adipokine in obesity. We report that IL‐19 is expressed in WAT. Utilizing lean Il19 −/− knockout mice, we found that IL‐19 deficiency causes significantly reduced tissue vascularization, significantly increased adipose tissue hypoxia, fibrosis, and inflammation, as well as adipocyte hypertrophy. Moreover, lean Il19 −/− knockout mice fed a standard diet developed glucose intolerance and insulin resistance. Wild‐type mice with diet‐induced obesity also developed reduced vascularization and inflammation in WAT, along with glucose intolerance and insulin resistance. Treatment of wild‐type obese mice with recombinant IL‐19 improved vascularization, attenuated WAT inflammation, and reduced glucose intolerance. Mechanistic studies in vitro demonstrated that IL‐19 increases glucose uptake in cultured adipocytes, including human adipocytes. These metabolic actions of IL‐19 were linked to upregulation of the IRS2 and GLUT‐4 expression and function. Overall, these data are the first to demonstrate that endogenous anti‐inflammatory interleukins can be effectively used to uncouple inflammation from angiogenesis, thus preserving WAT metabolic function in obesity.