The effects of targeted disruption of a gene encoding rate-limiting enzyme of the TCA Cycle on mice

为了从根本上解决糖尿病等代谢性疾病，有必要重新评估三羧酸循环的意义，三羧酸循环是最重要的、非常高效的代谢途径。为了研究抑制周期的效果，在小鼠中破坏了编码柠檬酸合成酶(CS)的基因，柠檬酸合成酶是周期的限速酶之一。纯合子(CS-/-)小鼠表现出早期胚胎致死性，而杂合子(CS+/-)小鼠在每个mRNA、蛋白质和酶活性水平上都显示出CS基因的部分表达。野生型与CS+/-小鼠体重、基础代谢率、血压、空腹血糖/胰岛素、血脂水平无明显差异，但呼吸商(呼吸交换比)显著低于CS+/-小鼠，而血清乙酰乙酸酯水平显著高于CS+/-小鼠。对野生型和CS+/-小鼠进行1-2个月的高脂高糖饮食，在静脉葡萄糖负荷后，CS+/-小鼠的血糖反应与野生型小鼠相比无明显差异。小鼠被认为是研究胰岛素抵抗导致能量代谢紊乱的机制的有用模型。

In order to explore the fundamental solution over metabolic disorders like diabetes, it is necessary to re-evaluate the significance of tricarboxylic acid (TCA) cycle, the most important metabolic pathway with very high efficiency. To investigate the effects of inhibiting the cycle, the gene encoding citrate synthase (CS), one of rate-limiting enzymes of the cycle, was disrupted in mice. Homozygous (CS-/-) mice showed early embryonic lethality but heterozygous mice (CS+/-) showed partial expression of the CS gene in each of the mRNA, protein, and enzyme activity levels. Whereas there were no differences in weight, basal metabolic rate, blood pressure, fasting plasma glucose/insulin levels, serum lipid levels between wild-type and CS+/-mice, it is clarified that respiratory quotient (respiratory exchange ratio) was significantly lower and serum acetoacetate levels were significantly higher in CS+/-mice. High-fat high-sugar diet of one or two months for both wild-type and CS+/-mice resulted in marked blunted plasma response after intravenous glucose load without any differences in glucose responses in CS+/-mice compared with wild-type mice. It is thought that the mouse could be a useful model to investigate the mechanisms of insulin resistance underlying energy metabolism disorders.