共伴侣蛋白 FKBP51在高脂诱导肥胖中的作用

摘要

目的：通过FKBP51基因敲除小鼠模型和细胞脂肪分化模型，探究FKBP51在高脂诱导肥胖中的机制。方法4周龄雄性野生型和FKBP51基因敲除小鼠以普通或高脂饲料单只单笼喂养6周，每周记录小鼠体重和饮食量，应用MM-100代谢笼系统，监测各组小鼠24 h内氧气消耗量、二氧化碳产生量、呼吸交换率和产热量的变化，对上述小鼠肝脏组织进行油红O染色，同时检测肝脏和脂肪组织代谢相关基因的表达情况。同时对取自野生型和FKBP51基因敲除小鼠的永生化成纤维细胞（ MEF）进行脂肪诱导分化，观察FKBP51缺失对脂肪分化的影响。结果高脂饮食诱导后，两种基因型小鼠饮食量无明显变化，但与野生型小鼠相比，FKBP51基因敲除小鼠体重明显减轻，肝脏中脂滴减少。 FKBP51基因敲除小鼠在基础和高脂诱导条件下，氧气消耗量、二氧化碳产生量、呼吸交换率以及产热量均高于野生型小鼠，肝脏中糖异生相关酶PEPCK、G6Pase等表达上调，脂肪中能量代谢相关基因UCP-1等表达上调。此外，FKBP51基因缺失的MEF诱导脂肪分化，细胞内脂滴明显少于野生型MEF细胞。结论 FKBP51基因在脂肪合成和能量代谢方面起着重要作用，因此FKBP51基因缺失小鼠能够抵制高脂诱导的肥胖。%Objective The goal of this study is to understand the function of FKBP51 in resistant to high fat diet-induced obesity using FKBP51 knockout ( KO) mice and in vitro adipocyte differentiation.Methods Four-week old male FKBP51 KO and wild type ( WT) mice were fed separately with regular or high fat diet for 6 weeks.The body weight and food consumption were recorded weekly, the energy expenditure differences ( O2 consumption, CO2 production, respiratory exchange ratio, and heat production) of each group were monitored using the MM-100 metabolism cages system for 24 hours, then the liver from the above animals were stained with the Oil red-O to detect the lipid accumulation and the expression of metabolic genes.In addition, induction of adipocyte differentiation of immortalized MEF cells from WT and FKBP51 KO mice were used to observe the effect of FKBP51 gene on lipogenesis.Results Compared to WT mice, FKBP51 KO mice has less weight increment, and less lipid accumulation in the liver, but with no difference on food consumption during high-fat diet fed.Moreover, FKBP51 KO mice exhibited more O2 consumption, CO2 production and heated production under both RD and HF diet conditions.The PEPCK, G6Pase and UCP-1 genes up-regulation.In addition, lipid content was reduced in FKBP51 gene deficient MEF cells after adipocyte differentiation.Conclusions The FKBP51 gene plays an important role in high fat diet-induced obesity through the energy metabolism enhancement and lipogenesis inhibition.