Zhou Mei-Cen, Yu Ping, Sun Qi, Li Yu-Xiu
Department of Endocrinology Key Laboratory of Endocrinology Ministry of Health Peking Union Medical College Hospital Beijing China.
Department of Pharmacy the Third People's Hospital Qinhuangdao China.
J Diabetes Investig. 2016 Mar;7(2):179-89. doi: 10.1111/jdi.12402. Epub 2015 Sep 2.
AIMS/INTRODUCTION: Uncoupling protein 2 (UCP2), which was an important mitochondrial inner membrane protein associated with glucose and lipid metabolism, widely expresses in all kinds of tissues including hepatocytes. The present study aimed to explore the impact of UCP2 deficiency on glucose and lipid metabolism, insulin sensitivity and its effect on the liver-associated signaling pathway by expression profiling analysis.
Four-week-old male UCP2-/- mice and UCP2+/+ mice were randomly assigned to four groups: UCP2-/- on a high-fat diet, UCP2-/- on a normal chow diet, UCP2+/+ on a high-fat diet and UCP2+/+ on a normal chow diet. The differentially expressed genes in the four groups on the 16th week were identified by Affymetrix gene array.
The results of intraperitoneal glucose tolerance test and insulin tolerance showed that blood glucose and β-cell function were improved in the UCP2-/- group on high-fat diet. Enhanced insulin sensitivity was observed in the UCP2-/- group. The differentially expressed genes were mapped to 23 pathways (P < 0.05). We concentrated on the 'peroxisome proliferator-activated receptor (PPAR) signaling pathway' (P = 3.19 × 10(-11)), because it is closely associated with the regulation of glucose and lipid profiles. In the PPAR signaling pathway, seven genes (PPARγ, Dbi, Acsl3, Lpl, Me1, Scd1, Fads2) in the UCP2-/- mice were significantly upregulated.
The present study used gene arrays to show that activity of the PPAR signaling pathway involved in the improvement of glucose and lipid metabolism in the liver of UCP2-deficient mice on a long-term high-fat diet. The upregulation of genes in the PPAR signaling pathway could explain our finding that UCP2 deficiency ameliorated insulin sensitivity. The manipulation of UCP2 protein expression could represent a new strategy for the prevention and treatment of diabetes.
目的/引言：解偶联蛋白2（UCP2）是一种与葡萄糖和脂质代谢相关的重要线粒体内膜蛋白，广泛表达于包括肝细胞在内的各种组织中。本研究旨在通过表达谱分析探讨UCP2缺乏对葡萄糖和脂质代谢、胰岛素敏感性的影响及其对肝脏相关信号通路的作用。
将4周龄雄性UCP2 - / - 小鼠和UCP2 + / + 小鼠随机分为四组：高脂饮食的UCP2 - / - 组、正常饮食的UCP2 - / - 组、高脂饮食的UCP2 + / + 组和正常饮食的UCP2 + / + 组。通过Affymetrix基因芯片鉴定第16周时四组中差异表达的基因。
腹腔葡萄糖耐量试验和胰岛素耐量试验结果表明，高脂饮食的UCP2 - / - 组血糖和β细胞功能得到改善。UCP2 - / - 组观察到胰岛素敏感性增强。差异表达基因被映射到23条信号通路（P < 0.05）。我们重点关注“过氧化物酶体增殖物激活受体（PPAR）信号通路”（P = 3.19×10 - 11），因为它与葡萄糖和脂质代谢的调节密切相关。在PPAR信号通路中，UCP2 - / - 小鼠中的七个基因（PPARγ、Dbi、Acsl3、Lpl、Me1、Scd1、Fads2）显著上调。
本研究使用基因芯片表明，长期高脂饮食的UCP2缺陷小鼠肝脏中，PPAR信号通路的活性参与了葡萄糖和脂质代谢的改善。PPAR信号通路中基因的上调可以解释我们发现的UCP2缺乏改善胰岛素敏感性这一现象。操纵UCP2蛋白表达可能代表一种预防和治疗糖尿病的新策略。
