BackgroundObesity causes a functional disorder of the white adipose tissue (WAT). Hypertrophic adipocytes, immune cells, and dysfunctional endothelium of the WAT microcirculation all contribute to cytokine secretion, which causes a state of chronic low-grade systemic inflammation with peripheral IR, termed “metaflammation”. Inflammatory cytokines downregulate the activity of the insulin sensitive glucose transporter GLUT4. GLUT4 expression in WAT plays a critical role in whole-body insulin sensitivity and glucose homeostasis, two metabolic parameters heavily implicated in cardiovascular disease. We tested the hypothesis that IL-19, a cytokine uniquely provided with immunomodulatory and pro-angiogenic action, directly stimulates glucose uptake in adipocytes thus improving whole-body insulin sensitivity.ResultsWe report that IL-19 is expressed in adipose tissue at both the transcript and protein level and its expression is increased in inflamed visceral adipose tissue but not subcutaneous adipose tissue (p<0.001). Utilizing Il19 knockout mice, we found the loss of IL-19 leads to a metabolic phenotype characterized by reduced glucose and insulin tolerance, reduced GLUT4 mRNA levels, along with increased adipocyte hypertrophy and adipose tissue fibrosis both in response to standard chow diet and chronic high fat diet (p<0.05). Treatment of diet induced obese (DIO) WT mice with 10 ng/g IL-19 for 7 consecutive days reduced glucose and insulin intolerance (p<0.05). In primary WT murine epididymal adipocytes the addition of IL-19 increased glucose uptake (p<0.01), a phenomenon that was not observed with the other IL-20 sub-family members, IL-20 and IL-24, who share the same receptor. Fasentin, a GLUT4 inhibitor, reduced glucose uptake in response to IL-19 stimulation in primary murine epididymal adipocytes (p<0.05) further confirming a role for GLUT4 in the primary metabolic action of IL-19.ConclusionsThese data are the first to demonstrate the primary metabolic action of IL-19 on adipose tissue glucose uptake, a well-established player in systemic insulin sensitivity. Further studies are necessary to fully understand the role that endogenous and pharmacological doses of IL-19 might play in cardiometabolic disorders.