The major urinary protein gene cluster knockout mouse as a novel model for translational metabolism research [RNAseq]

Scientific evidence suggests that not only murine scent communication is regulated by major urinary proteins, but that their expression may also vary in response to metabolism via a yet unknown mechanism. Major urinary proteins are expressed mainly in the liver, showing a sexually dimorphic pattern with substantially higher expression in males. Here, we investigate the metabolic implications of a major urinary protein knockout in twelve-week-old male and female C57BL/6N mice during ad libitum feeding. Despite both sexes of major urinary protein knockout mice displayed numerically increased body weight and visceral adipose tissue proportions compared to sex-matched wildtype mice, the main genotype-specific metabolic differences were observed exclusively in males. Male major urinary protein knockout mice exhibited plasma and hepatic lipid accumulation accompanied by a hepatic transcriptome indicating an activation of lipogenesis. These findings match the higher major urinary protein expression in male compared to female wildtype mice, suggesting a more distinct reduction in energy requirements in male compared to female major urinary protein knockout mice. The observed sex-specific anabolic phenotype confirms a role of major urinary protein in metabolism and, since major urinary proteins are not expressed in humans, suggests the major urinary protein knockout mouse as a potential alternative model for translational metabolism research which needs to be further elucidated. Differential gene expression analysis in male and female major urinary protein knockout mice and their wildtype littermates科学研究证据表明，主要尿蛋白（major urinary proteins）不仅调控小鼠的气味通讯，其表达还可通过尚未明确的机制响应代谢状态发生改变。主要尿蛋白主要在肝脏中表达，呈现性别二态性模式，雄性个体的表达量显著更高。本研究以12周龄的C57BL/6N雌雄小鼠为对象，在自由采食条件下，探究主要尿蛋白敲除对机体代谢的影响。尽管与同性别野生型小鼠相比，主要尿蛋白敲除小鼠（雌雄均）的体重及内脏脂肪组织占比均呈现升高趋势，但基因型特异性的核心代谢差异仅在雄性个体中被观测到。雄性主要尿蛋白敲除小鼠表现出血浆与肝脏脂质蓄积，同时肝脏转录组显示脂肪生成通路被激活。上述发现与野生型小鼠中雄性主要尿蛋白表达量更高的现象一致，提示相较于雌性敲除小鼠，雄性主要尿蛋白敲除小鼠的能量需求降幅更为显著。本次观测到的性别特异性合成代谢表型，证实了主要尿蛋白在代谢调控中的功能；由于人类体内不表达主要尿蛋白，这一结果提示主要尿蛋白敲除小鼠可作为转化代谢研究的潜在替代模型，相关机制仍有待进一步阐明。本研究针对雌雄主要尿蛋白敲除小鼠及其同窝野生型小鼠开展了差异基因表达分析。