Expression profiles of angiopoietin-related growth factor (AGF) in obese and hyperleptinemic model

의학과/박사[한글] [영문]A novel cytokine family named as angiopoietin-like proteins (Angptls) has been reported to closely regulate lipid, glucose, and energy metabolism. Angiopoietin-related growth factor (AGF), an angiopoietin-like protein6 (Angptl6), cloned in human and mice that functions as a growth factor for epidermal proliferation, remodeling, and regeneration. Recently, it has been known that Angptl6/AGF antagonizes obesity and insulin resistance resulting from increased energy expenditure but their physiologic roles still remain unclear. The purpose of this study is to examine the expression profiles of Angptls, particularly Angptl6/AGF, in high-fat diet (HFD)-induced obese and hyperleptinemic mice. HFD containing 45 % fats for 12 weeks increased visceral fat mass and serum transaminase levels. The size of white adipose tissue and fat accumulation in liver were increased in the HFD group. In addition, HFD caused an impaired glucose tolerance, and increased the expression levels of pro-inflammatory cytokines in epididymal fat. There is an approximately 4-fold increase in the level of serum leptin in the HFD compared to control. Serum levels of adiponectin and RBP4 were also increased in HFD group (approximately 7% and 4% increase, respectively). Conversely, the exercise training (12 weeks) markedly decreased body weight, size of visceral fat, and hepatic fat accumulation with HFD mice. Oxygen consumption was increased, whereas blood pressure and pulse rate were decreased in exercised mice. Serum adiponectin and leptin concentration were significantly decreased in exercised mice. Among Angptls, serum concentration of Angptl3 and the hepatic expression level of Angptl4 in HFD mice were lower than those in control. Interestingly, hepatic expression of Angptl6/AGF was significantly increased in HFD group. Contrary to the effect of HFD, exercise training increased the serum Angptl3 and the Angptl4 expression, but reduced the Angptl6/AGF expression. To confirm whether the expression levels of Angptls were modulated by leptin, leptin was injected (2 μg/g twice daily i.p. for 7 days) to maintain high blood level. Food intake, body weight, fasting blood glucose, and triglycerides were decreased time-dependently in leptin-injected mice. At the end of injection, we confirmed the more than 100-fold higher level of serum leptin in leptin-injected mice than that in control. Hyperleptinemic mice had less serum Angptl3 concentration and lower hepatic expression levels of Angptl3 and Angptl4 than control. The expression of Angptl6/AGF was significantly increased in liver and epididymal fat tissue in leptin-injected mice. In primary hepatocytes, in vitro application of leptin (10 ng/ml for 24 hours) elevated the expression of Angptl6/AGF, while reduced the expression of Angptl3 and Angptl4.In conclusion, HFD-induced obese mice as well as hyperleptinemic mice had elevated expression level of Angptl6/AGF accompanied with decreased levels of Angptl3 and Angptl4. Based on our results, we can suggest that the up-regulation of Angptl6/AGF might be a compensatory change which is mediated by high leptin level in HFD mice.prohibitio