PDF(Pubmed)
Abstract：
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.
Obesity rates are climbing worldwide, leading to an increase in associated conditions such as type 2 diabetes. While new pharmaceutical approaches are available to help individuals manage their weight, many patients do not respond to them or experience prohibitive side effects. Identifying alternative treatments will likely require pinpointing the genes and molecular actors involved in the biological processes that control weight regulation. Previous research suggests that a protein known as SPAG7 could help shape how mice use and store the energy they extract from food. Flaherty et al. therefore set out to investigate the role this protein plays in the body. To do so, they created a line of mice born without SPAG7, which they monitored closely throughout life. These animals were underweight at birth and did not eat more than other mice, yet they were obese as adults. Their ability to exercise was reduced, their muscles were weaker and contained fibers with functional defects. The mice also exhibited biological changes associated with the onset of diabetes. Yet deleting SPAG7 during adulthood led to no such changes; these mice maintained normal muscle function and body weight. Closely examining how SPAG7-deficient mice developed in the womb revealed placental defects which likely caused these animals to receive fewer nutrients from their mother. Such early-life deprivation is known to be associated with the body shifting towards maximizing its use of resources and privileging fat storage, even into and throughout adulthood. By shedding light on the biological role of SPAG7, the work by Flaherty et al. helps to better understand how developmental events can increase the likelihood of obesity later in life. Further investigations are now needed to explore whether this knowledge could help design interventions relevant to human health.
Obesity rates are climbing worldwide, leading to an increase in associated conditions such as type 2 diabetes. While new pharmaceutical approaches are available to help individuals manage their weight, many patients do not respond to them or experience prohibitive side effects. Identifying alternative treatments will likely require pinpointing the genes and molecular actors involved in the biological processes that control weight regulation. Previous research suggests that a protein known as SPAG7 could help shape how mice use and store the energy they extract from food. Flaherty et al. therefore set out to investigate the role this protein plays in the body. To do so, they created a line of mice born without SPAG7, which they monitored closely throughout life. These animals were underweight at birth and did not eat more than other mice, yet they were obese as adults. Their ability to exercise was reduced, their muscles were weaker and contained fibers with functional defects. The mice also exhibited biological changes associated with the onset of diabetes. Yet deleting SPAG7 during adulthood led to no such changes; these mice maintained normal muscle function and body weight. Closely examining how SPAG7-deficient mice developed in the womb revealed placental defects which likely caused these animals to receive fewer nutrients from their mother. Such early-life deprivation is known to be associated with the body shifting towards maximizing its use of resources and privileging fat storage, even into and throughout adulthood. By shedding light on the biological role of SPAG7, the work by Flaherty et al. helps to better understand how developmental events can increase the likelihood of obesity later in life. Further investigations are now needed to explore whether this knowledge could help design interventions relevant to human health.
摘要：
从正向诱变筛选中发现与肥胖相关的突变，我们发现Spag7基因突变与小鼠代谢功能障碍相关.这里,我们显示SPAG7KO小鼠出生时更小，并且在成年期出现肥胖和葡萄糖耐受不良。这种肥胖不是由饮食过多引起的，而是能量消耗的减少。由于线粒体功能受损,KO动物还表现出运动耐量和肌肉功能降低。此外，发育中的胚胎缺乏SPAG7会导致宫内生长受限，由胎盘功能不全引起的，可能是由于胎盘连接区的异常发育。这种不足导致子宫内缺乏SPAG7的胎儿丢失，并降低了存活者的出生体重。我们假设在SPAG7KO动物的发育过程中，“节俭表型”根深蒂固，导致成人肥胖。总的来说，这些结果表明SPAG7对于以后的胚胎发育和能量稳态至关重要。
全世界的肥胖率都在攀升,导致相关疾病如2型糖尿病的增加。虽然有新的药物方法可以帮助个人控制体重，许多患者对它们没有反应或经历过令人望而却步的副作用。确定替代治疗可能需要精确定位控制体重调节的生物过程中涉及的基因和分子因子。先前的研究表明，一种被称为SPAG7的蛋白质可以帮助塑造小鼠如何使用和储存它们从食物中提取的能量。Flaherty等人。因此，着手研究这种蛋白质在体内的作用。要做到这一点，他们创造了一系列没有SPAG7出生的小鼠，他们在整个生命中密切监测。这些动物出生时体重不足，没有其他老鼠吃得更多，然而他们成年后肥胖。他们的运动能力下降了，他们的肌肉较弱，含有功能缺陷的纤维。小鼠还表现出与糖尿病发作相关的生物学变化。然而，在成年期删除SPAG7并没有导致这种变化；这些小鼠保持正常的肌肉功能和体重。仔细检查子宫中缺乏SPAG7的小鼠如何发现胎盘缺陷，这可能导致这些动物从母亲那里获得更少的营养。众所周知，这种早期生活剥夺与身体转向最大限度地利用资源和特权脂肪储存有关。甚至成年后。通过阐明SPAG7的生物学作用，Flaherty等人的工作。有助于更好地了解发育事件如何增加以后生活中肥胖的可能性。现在需要进一步的调查来探索这些知识是否可以帮助设计与人类健康相关的干预措施。
全世界的肥胖率都在攀升,导致相关疾病如2型糖尿病的增加。虽然有新的药物方法可以帮助个人控制体重，许多患者对它们没有反应或经历过令人望而却步的副作用。确定替代治疗可能需要精确定位控制体重调节的生物过程中涉及的基因和分子因子。先前的研究表明，一种被称为SPAG7的蛋白质可以帮助塑造小鼠如何使用和储存它们从食物中提取的能量。Flaherty等人。因此，着手研究这种蛋白质在体内的作用。要做到这一点，他们创造了一系列没有SPAG7出生的小鼠，他们在整个生命中密切监测。这些动物出生时体重不足，没有其他老鼠吃得更多，然而他们成年后肥胖。他们的运动能力下降了，他们的肌肉较弱，含有功能缺陷的纤维。小鼠还表现出与糖尿病发作相关的生物学变化。然而，在成年期删除SPAG7并没有导致这种变化；这些小鼠保持正常的肌肉功能和体重。仔细检查子宫中缺乏SPAG7的小鼠如何发现胎盘缺陷，这可能导致这些动物从母亲那里获得更少的营养。众所周知，这种早期生活剥夺与身体转向最大限度地利用资源和特权脂肪储存有关。甚至成年后。通过阐明SPAG7的生物学作用，Flaherty等人的工作。有助于更好地了解发育事件如何增加以后生活中肥胖的可能性。现在需要进一步的调查来探索这些知识是否可以帮助设计与人类健康相关的干预措施。
