SPAG7 deletion causes intrauterine growth restriction, resulting in adulthood obesity and metabolic dysfunction

From a forward mutagenetic screen to discover mutations associated with obesity, we identified mutations in the spag7 gene linked to metabolic dysfunction in mice. Here we show that SPAG7 KO mice are born smaller and develop obesity and glucose intolerance in adulthood. This obesity does not stem from hyperphagia, but a decrease in energy expenditure. The KO animals also display reduced exercise tolerance and muscle function due to impaired mitochondrial function. Furthermore, SPAG7-deficiency in developing embryos leads to intrauterine growth restriction, brought on by placental insufficiency, likely due to abnormal development of the placental junctional zone. This insufficiency leads to loss of SPAG7-deficient fetuses in utero and reduced birth weights of those that survive. We hypothesize that a "thrifty phenotype" is ingrained in SPAG7 KO animals during development that leads to adult obesity. Collectively, these results indicate that SPAG7 is essential for embryonic development and energy homeostasis later in life. To investigate the role of SPAG7 in skeletal muscle function, gastrocnemius muscle was isolated from WT and SPAG-deficient male and female mice. 28-week-old WT and SPAG7 KO animals were sacrificed and gastrocnemius muscle was snap-frozen in liquid nitrogen, before preparation for RNAseq We then performed gene expression profiling analysis using data obtained from bulk RNAseq.本研究通过正向诱变筛选以挖掘与肥胖相关的突变，在小鼠体内鉴定出与代谢功能障碍相关的spag7基因（spag7）突变。研究证实，SPAG7敲除（SPAG7 KO）小鼠出生时体型偏小，并在成年后发展为肥胖与葡萄糖耐受不良。该肥胖并非源于摄食过多，而是能量消耗降低所致。此类敲除小鼠还因线粒体功能受损，表现出运动耐力与肌肉功能下降。此外，发育胚胎中的SPAG7缺失会引发宫内生长受限，该情况由胎盘功能不全介导，而胎盘功能不全可能源于胎盘交界区的发育异常。这种功能不全不仅会造成SPAG7缺失胚胎在子宫内死亡，存活个体的出生体重也会降低。我们提出假说：SPAG7敲除小鼠在发育阶段便已固化的“节俭表型”，是其成年后出现肥胖的核心诱因。综上，本研究结果表明SPAG7对胚胎发育以及成年后的能量稳态均至关重要。为探究SPAG7在骨骼肌功能中的作用，我们从野生型（WT）及SPAG7缺失的雌雄小鼠体内分离出腓肠肌。对28周龄的野生型与SPAG7敲除小鼠实施安乐死后，将分离得到的腓肠肌置于液氮中快速冷冻，以待进行RNA测序（RNAseq）样本制备。随后我们基于批量RNA测序（bulk RNAseq）获得的数据开展了基因表达谱分析。