Jollet Maxence, Tramontana Flavia, Jiang Lake Q, Borg Melissa L, Savikj Mladen, Kuefner Michael S, Massart Julie, de Castro Barbosa Thais, Mannerås-Holm Louise, Checa Antonio, Pillon Nicolas J, Chibalin Alexander V, Björnholm Marie, Zierath Juleen R
Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
Metabolism. 2024 Sep;158:155939. doi: 10.1016/j.metabol.2024.155939. Epub 2024 Jun 4.
Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C signaling by converting DAG to phosphatidic acid. DGKδ (type II isozyme) downregulation causes insulin resistance, metabolic inflexibility, and obesity. Here we determined whether DGKδ overexpression prevents these metabolic impairments.
We generated a transgenic mouse model overexpressing human DGKδ2 under the myosin light chain promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG mice and wild-type littermates fed chow or high-fat diet (HFD). Mice were also provided free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes.
DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance and increased skeletal muscle glycogen content. DGKδ TG mice were protected against HFD-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulated the beneficial effects of exercise on metabolic outcomes. DGKδ overexpression and exercise had a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle revealed common gene ontology signatures of exercise and DGKδ overexpression that were related to lipid storage, extracellular matrix, and glycerophospholipids biosynthesis pathways.
Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against HFD-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles.
二酰基甘油激酶（DGK）同工型催化一种酶促反应，该反应去除二酰基甘油（DAG），从而通过将DAG转化为磷脂酸来终止蛋白激酶C信号传导。DGKδ（II型同工酶）下调会导致胰岛素抵抗、代谢灵活性降低和肥胖。在此，我们确定了DGKδ过表达是否能预防这些代谢障碍。
我们构建了一种在肌球蛋白轻链启动子下过表达人DGKδ2的转基因小鼠模型（DGKδ TG）。我们对喂食普通饲料或高脂饮食（HFD）的DGKδ TG小鼠和野生型同窝小鼠进行了深入的代谢表型分析。还为小鼠提供了自由使用跑步轮的机会，以研究DGKδ过表达对运动诱导的代谢结果的影响。
DGKδ TG小鼠比野生型同窝小鼠更瘦，葡萄糖耐量改善，骨骼肌糖原含量增加。DGKδ TG小鼠对HFD诱导的葡萄糖不耐受和肥胖具有保护作用。DGKδ TG小鼠附睾脂肪减少，脂肪分解增强。令人惊讶的是，DGKδ过表达重现了运动对代谢结果的有益影响。DGKδ过表达和运动对体重减轻具有协同作用。对骨骼肌的微阵列分析揭示了运动和DGKδ过表达的共同基因本体特征，这些特征与脂质储存、细胞外基质和甘油磷脂生物合成途径有关。
DGKδ过表达诱导骨骼肌和脂肪组织的适应性变化，从而预防HFD诱导的肥胖。DGKδ过表达重现了运动诱导的对能量稳态和骨骼肌基因表达谱的适应性变化。
