Functional Polymorphism of IL-1 Alpha and Its Potential Role in Obesity in Humans and Mice

Proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. IL-1α is one of the proinflammatory cytokines; however, it has not been clarified whether IL-1α may also cause obesity. In this study, we investigated whether polymorphisms in IL-1α contribute to human obesity. A total of 260 obese subjects were genotyped for IL-1α C-889T (rs1800587) and IL-1α G+4845T (rs17561). Analyses of genotype distributions revealed that both IL-1α polymorphisms C-889T (rs1800587) and G+4845T (rs17561) were associated with an increase in body mass index in obese healthy women. In addition, the effect of rs1800587 on the transcriptional activity of IL-1α was explored in pre-adipocyte 3T3-L1 cells. Significant difference was found between the rs1800587 polymorphism in the regulatory region of the IL-1α gene and transcriptional activity. We extended these observations in vivo to a high-fat diet-induced obese mouse model and in vitro to pre-adipocyte 3T3-L1 cells. IL-1α levels were dramatically augmented in obese mice, and triglyceride was increased 12 hours after IL-1α injection. Taken together, IL-1α treatment regulated the differentiation of preadipocytes. IL-1α C-889T (rs1800587) is a functional polymorphism of IL-1α associated with obesity. IL-1α may have a critical function in the development of obesity.脂肪组织分泌的促炎细胞因子，是肥胖相关并发症发病的重要介导因素。白细胞介素-1α（Interleukin-1α, IL-1α）属于此类促炎细胞因子，但目前尚未明确其是否同样可诱发肥胖。本研究旨在探究IL-1α基因多态性与人类肥胖发生的相关性。本研究共纳入260名肥胖受试者，对其IL-1α基因的C-889T（rs1800587）与G+4845T（rs17561）两个位点开展基因分型检测。基因型分布分析结果显示，在肥胖健康女性群体中，IL-1α的上述两个多态性位点均与体质量指数（Body Mass Index, BMI）升高显著相关。此外，本研究在前体脂肪细胞3T3-L1中，探究了rs1800587位点对IL-1α转录活性的调控作用，发现IL-1α基因调控区的该多态性位点可显著影响其转录活性。本研究进一步将上述实验发现拓展至体内与体外体系：体内实验采用高脂饮食诱导的肥胖小鼠模型，体外实验则沿用前体脂肪细胞3T3-L1细胞系。结果表明，肥胖小鼠体内的IL-1α水平显著升高；且在IL-1α注射后12小时，小鼠体内甘油三酯（Triglyceride, TG）水平显著上升。综合上述结果可知，IL-1α可调控前体脂肪细胞的分化过程。IL-1α C-889T（rs1800587）是与肥胖相关的IL-1α功能性基因多态性位点。IL-1α可能在肥胖的发生发展过程中发挥关键作用。