高脂饮食诱导的肥胖(HFD)是一种多因素疾病,生理,行为,和环境成分。果蝇已成为一种有效的代谢性疾病模型。胞苷5'-三磷酸合成酶(CTPS)是CTP从头合成的重要酶,控制CTP的细胞水平和磷脂合成速率。众所周知,CTPS会形成丝状结构,称为胞嘧啶,在细菌中发现,古细菌,和真核生物。我们的研究表明,CTPS通过在脂肪体中发挥作用,在调节果蝇的体重和饥饿抗性方面至关重要。HFD诱导的肥胖导致CTPS转录增加,并延长幼虫脂肪细胞中的胞质。消耗脂肪体内的CTPS可以预防HFD引起的肥胖,包括体重增加,脂肪细胞扩增,和脂质积累,通过抑制PI3K-Akt-SREBP轴。此外,CTPS的显性阴性形式也阻止了脂肪细胞的扩增和脂肪生成基因的下调.这些发现不仅建立了CTPS和脂质稳态之间的功能联系,而且突出了CTPS操作在治疗HFD诱导的肥胖中的潜在作用。
高肥胖率导致糖尿病和心血管疾病等慢性疾病的发病率增加,从而造成了全球健康负担。解决这个问题很复杂,因为它受到许多因素的影响,包括遗传学,行为和环境。为了更好地了解在更简单的环境中导致代谢问题的生化变化,科学家可以在实验室里研究果蝇。这些昆虫与人类共享许多基因,并且对高脂肪饮食具有相似的反应。以前的研究发现了一种酶,称为CTP合酶(CTPS),哺乳动物的肝脏和脂肪组织大量产生,果蝇的等价物,被称为脂肪的身体。多个CTPS分子可以结合形成长链蛋白质,称为胞嘧啶,在从人类到细菌的生物体中都可以看到。最近的结果表明,果蝇相当于CTPS会驱动脂肪细胞粘在一起,这是维持和形成脂肪组织所必需的。然而,目前尚不清楚改变CTPS水平是否会影响对高脂肪饮食的反应。为了解决这个问题,Liu,张,Wang等人。研究了高脂肪饮食的果蝇,表明这增加了CTPS的产量。当苍蝇被治疗以耗尽脂肪体内的CTPS水平时,他们体重增加较少,脂肪细胞更小,体内脂肪含量更低。转基因果蝇的CTPS版本无法形成胞质,也显示出更少的肥胖迹象,表明酶如何影响对膳食脂肪的反应。这些发现进一步暗示CTPS是肥胖的原因,并有助于理解其作用。然而,这是否也适用于人类还有待观察。如果是这样的话,阻断CTPS活性的药物有助于减少高脂肪饮食对公众健康的影响.
Obesity induced by high-fat diet (HFD) is a multi-factorial disease including genetic, physiological, behavioral, and environmental components. Drosophila has emerged as an effective metabolic disease model. Cytidine 5\'-triphosphate synthase (CTPS) is an important enzyme for the de novo synthesis of CTP, governing the cellular level of CTP and the rate of phospholipid synthesis. CTPS is known to form filamentous structures called cytoophidia, which are found in bacteria, archaea, and eukaryotes. Our study demonstrates that CTPS is crucial in regulating body weight and starvation resistance in Drosophila by functioning in the fat body. HFD-induced obesity leads to increased transcription of CTPS and elongates cytoophidia in larval adipocytes. Depleting CTPS in the fat body prevented HFD-induced obesity, including body weight gain, adipocyte expansion, and lipid accumulation, by inhibiting the PI3K-Akt-SREBP axis. Furthermore, a dominant-negative form of CTPS also prevented adipocyte expansion and downregulated lipogenic genes. These findings not only establish a functional link between CTPS and lipid homeostasis but also highlight the potential role of CTPS manipulation in the treatment of HFD-induced obesity.
The high rate of obesity has created a global health burden by leading to increased rates of chronic diseases like diabetes and cardiovascular disease. Tackling this issue is complicated as it is influenced by many factors, including genetics, behaviour and environment. To better understand the biochemical changes that underly metabolic issues in a simpler setting, scientists can study fruit flies in the laboratory. These insects share many genes with humans and have similar responses to a high-fat diet. Previous research identified an enzyme, called CTP synthase (CTPS), which is produced in large amounts by the liver and fat tissue in mammals, and the equivalent in fruit flies, known as the fat body. Multiple CTPS molecules can combine to form long strands of protein called cytoophidia, which have been seen in organisms ranging from humans to bacteria. Recent results showed that the fruit fly equivalent of CTPS drives fat cells to stick together, which is necessary to maintain and form fat tissue. However, it is not clear if altering the levels of CTPS can affect the response to a high-fat diet. To address this, Liu, Zhang, Wang et al. studied fruit flies on a high-fat diet, showing that this increased the production of CTPS. When the flies were treated to deplete levels of CTPS in the fat body, they had less body weight gain, smaller fat cells and lower amounts of fats in the body. Genetically modified flies with a version of CTPS that was unable to form cytoophidia also showed fewer signs of obesity, indicating how the enzyme might influence the response to dietary fats. These findings further implicate CTPS in the cause of obesity and help to understand its role. However, it remains to be seen if this also applies to humans. If this is the case, drugs that block the activity of CTPS could help to reduce the impact of a high-fat diet on public health.