Diacylglycerol Kinase Delta Improves Glucose Clearance and Protects Against the Development of Obesity

Background and aim: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C (PKC) signaling by converting DAG to phosphatidic acid (PA). We have reported that downregulation of DGKδ (type II isozyme) causes peripheral insulin resistance, metabolic inflexibility, and obesity. Our aim was to determine whether overexpression of DGKδ protects against the development of metabolic impairments and obesity. Methods: We generated a transgenic mouse model overexpressing the human DGKδ2 isoform under the myosin light change promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG and wild-type mice fed chow or high-fat diet. Mice were also given free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes. Results: DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance, increased glycogen storage in skeletal muscle, and enhanced glucose uptake in white adipose tissue. Moreover, DGKδ TG mice were protected against high fat diet (HFD)-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat pad weight, and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulates the beneficial effects exercise on metabolic outcomes. DGKδ overexpression and exercise have a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle confirmed an overlap between genes associated with exercise and DGKδ overexpression. Gene ontology signatures of exercise and DGKδ overexpression were related to lipid storage, extracellular matrix, and glycogen biosynthesis pathways. Conclusion: We identify a role for DGKδ in glucose and energy homeostasis. Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against high fat diet-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles. wild-type sedentary (WT; n=5), MLC_DGKδ2 transgenic sedentary mice (TG; n=6), wild-type exercised (WT exercised; n=5) and MLC_DGKδ2 transgenic exercised mice (TG exercised; n=5)

背景与目的：二酰甘油激酶（Diacylglycerol kinase, DGK）同工型可催化酶促反应，将二酰甘油（Diacylglycerol, DAG）转化为磷脂酸（Phosphatidic acid, PA），从而清除DAG并终止蛋白激酶C（Protein kinase C, PKC）信号通路。本团队此前已报道，DGKδ（II型同工酶）的表达下调会引发外周胰岛素抵抗、代谢灵活性降低及肥胖。本研究旨在探究DGKδ过表达是否能够抵御代谢损伤与肥胖的发生发展。
方法：本研究构建了以肌球蛋白轻链启动子驱动人源DGKδ2同工型过表达的转基因小鼠模型（DGKδ TG）。对饲喂普通饲料或高脂饮食（High-fat diet, HFD）的DGKδ TG小鼠与野生型小鼠开展深度代谢表型分析。此外，让小鼠自由使用跑轮，以探究DGKδ过表达对运动诱导的代谢结局的影响。
结果：与野生型同窝小鼠相比，DGKδ TG小鼠体型更瘦，糖耐量得到改善，骨骼肌糖原储存量增加，白色脂肪组织的葡萄糖摄取能力增强。此外，DGKδ TG小鼠可抵御高脂饮食诱导的糖耐量受损与肥胖。DGKδ TG小鼠的附睾脂肪垫重量降低，脂肪分解能力增强。值得注意的是，DGKδ过表达可重现运动对代谢结局的有益作用。DGKδ过表达与运动在减轻体重方面具有协同效应。骨骼肌基因芯片分析证实，与运动相关的基因与DGKδ过表达相关基因存在重叠。运动与DGKδ过表达的基因本体论（Gene Ontology, GO）特征均与脂质储存、细胞外基质及糖原生物合成通路相关。
结论：本研究明确了DGKδ在糖与能量稳态中的作用。DGKδ过表达可诱导骨骼肌与脂肪组织发生适应性改变，从而抵御高脂饮食诱导的肥胖。DGKδ过表达可重现运动诱导的能量稳态适应性变化及骨骼肌基因表达谱改变。
实验分组：野生型静息组（WT；n=5）、MLC_DGKδ2转基因静息小鼠组（TG；n=6）、野生型运动组（WT运动组；n=5）及MLC_DGKδ2转基因运动小鼠组（TG运动组；n=5）