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

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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.