Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse

Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy metabolism. The objective of the present investigation was to determine the impact of Cyp4x1 on body weight and energy metabolism by developing a line of transgenic Cyp4x1-knock out mice. Mice were developed with a global knock-out of the gene; the full-length RNA was undetectable, and mice were viable and fertile. Both male and female Cyp4x1-knock out mice gained significantly more body weight on normal lab chow diet compared to control flox mice on the same genetic background. At necropsy, Cyp4x1-knock out male mice had significantly greater intra-abdominal fat deposits (P2 measures and crossing of infrared beams in metabolic cages were not significantly affected by the mutation in either gender. The respiratory exchange ratio was significantly decreased in male knock out mice (P2 was significantly decreased in both male and female Cyp4x1-knock out mice. We conclude that the Cyp4x1-knock out mouse strain demonstrates a mildly obese phenotype, consistent with the view that cytochrome P450 4x1 plays a role in regulating fat metabolism.细胞色素P450 4x1（Cytochrome P450 4x1, Cyp4x1）在大脑中呈高表达，但该蛋白的功能尚未明确。已有假说提出，其可调控脂肪酸代谢，并影响内源性大麻素信号系统的活性——已知该系统可调控食欲与能量代谢。本研究旨在通过构建Cyp4x1全身性敲除转基因小鼠品系，探究Cyp4x1对体重与能量代谢的影响。研究人员成功构建了该基因的全身性敲除小鼠模型，其全长RNA无法被检测到，且小鼠存活、可育。与同遗传背景的flox对照小鼠相比，在正常实验室饲料喂养条件下，雌雄Cyp4x1敲除小鼠的体重均显著升高。解剖结果显示，雄性Cyp4x1敲除小鼠的腹腔内脂肪沉积量显著增加；代谢笼中的P2指标与红外光束穿越次数在两种性别小鼠中均未因该基因突变出现显著变化。雄性敲除小鼠的呼吸交换比显著降低，而雌雄Cyp4x1敲除小鼠的P2指标均显著下降。本研究得出结论：Cyp4x1敲除小鼠品系呈现轻度肥胖表型，这与细胞色素P450 4x1参与调控脂肪代谢的观点相符。