Regulation of glucose/lipid metabolism and insulin sensitivity by interleukin-4

Objective: Abundant evidence has demonstrated that long-term cytokine-mediated inflammation is a risk factor for obesity and type 2 diabetes mellitus (T2DM). Our previous study reveals a significant association between promoter polymorphisms of Th2-derived cytokine interleukin-4 (IL-4) and T2DM, which suggests possible roles of IL-4 in metabolism. In this study, we focused on examining the putative regulation of glucose and lipid metabolism by IL-4. Methods: C57BL/6 mice were intraperitoneally injected with either adenovirus containing full-length IL-4 encoding gene (AdIL-4) or recombinant IL-4 for mimicking the status of transient and long-term IL-4 overexpression, respectively, and the effects of the overexpressed IL-4 to glucose/lipid metabolism and insulin sensitivity were subsequently investigated. Results: Our results reveal that IL-4 improves insulin sensitivity and glucose tolerance through upregulating Akt phosphorylation while attenuating GSK-3Β activities. IL-4 is also involved in lipid metabolism by inhibiting lipid accumulation in fat tissues, which lead to decreased weight gain and fat mass. Conclusions: Our results suggest that IL-4 regulates glucose and lipid metabolism by promoting insulin sensitivity, glucose tolerance and inhibiting lipid deposits. This study uncovers the novel roles of IL-4 in metabolism and provides new insights in the interaction between cytokines/immune responses, insulin sensitivity and metabolism.