FABP4-Cre Mediated Expression of Constitutively Active ChREBP Protects Against Obesity, Fatty Liver, and Insulin Resistance
FABP4-Cre Mediated Expression of Constitutively Active ChREBP Protects Against Obesity, Fatty Liver, and Insulin Resistance
复制标题
DOI：
10.1210/en.2015-1210
复制
发表时间：
2015-11-01
期刊：
影响因子：
4.8
通讯作者：
Chan, Lawrence
中科院分区：
文献类型：
--
作者：
Nuotio-Antar, Alli M.;Poungvarin, Naravat;Chan, Lawrence
碳水化合物反应元件结合蛋白（ChREBP）调节细胞葡萄糖和脂质稳态。虽然ChREBP在许多关键的代谢组织中高度表达，但ChREBP在大多数这些组织中的作用以及对全身葡萄糖和脂质代谢的影响尚不清楚。因此，我们产生了一个转基因小鼠，过表达的脂肪酸结合蛋白4-Cre驱动的启动子（FaChOX）的控制下的组成型活性的ChREBP亚型。当给予正常食物饮食或致肥胖西方饮食时，雄性FaChOX小鼠的体重增加变钝，但雌性FaChOX小鼠没有。在西方饮食喂养的FaChOX小鼠中，呼吸交换率增加，表明全身底物使用的转变有利于碳水化合物代谢。与对照组相比，西方饮食喂养的FaChOX小鼠显示出改善的胰岛素敏感性和葡萄糖耐量。与对照组相比，西方饮食喂养的FaChOX小鼠的肝脏甘油三酯含量降低，表明脂肪肝的保护作用。附睾脂肪组织表现出差异表达的基因参与分化，布朗宁，代谢，脂质稳态，和西方饮食喂养的FaChOX小鼠和对照之间的炎症。我们的研究结果支持ChREBP在调节脂肪细胞分化和脂肪组织代谢和炎症以及随之而来的肥胖和胰岛素抵抗风险中的作用。
Carbohydrate response element binding protein (ChREBP) regulates cellular glucose and lipid homeostasis. Although ChREBP is highly expressed in many key metabolic tissues, the role of ChREBP in most of those tissues and the consequent effects on whole-body glucose and lipid metabolism are not well understood. Therefore, we generated a transgenic mouse that over-expresses a constitutively active ChREBP isoform under the control of the fatty acid binding protein 4-Cre-driven promoter (FaChOX). Weight gain was blunted in male, but not female, FaChOX mice when placed on either a normal chow diet or an obesogenic Western diet. Respiratory exchange ratios were increased in Western diet-fed FaChOX mice, indicating a shift in whole-body substrate use favoring carbohydrate metabolism. Western diet-fed FaChOX mice showed improved insulin sensitivity and glucose tolerance in comparison with controls. Hepatic triglyceride content was reduced in Western diet-fed FaChOX mice in comparison with controls, suggesting protection from fatty liver. Epididymal adipose tissue exhibited differential expression of genes involved in differentiation, browning, metabolism, lipid homeostasis, and inflammation between Western diet-fed FaChOX mice and controls. Our findings support a role for ChREBP in modulating adipocyte differentiation and adipose tissue metabolism and inflammation as well as consequent risks for obesity and insulin resistance.