背景:肥胖及其相关并发症引起了公众的极大关注,揭示了代谢紊乱易感性中的性别差异,女性通常比男性对肥胖相关的代谢紊乱表现出更大的抵抗力。Sestrin2是参与代谢和能量平衡的关键蛋白质。这项研究旨在探索Sesn2基因敲除(KO)是否会加剧高脂饮食(HFD)诱导的雌性小鼠肥胖。
方法:对具有野生型(WT)和Sesn2KO的雌性小鼠进行12周的正常饮食或HFD方案。使用身体成分分析仪,测量了身体成分。生化检测包括葡萄糖,脂质,和肝功能测量,24小时尿白蛋白排泄。超声心动图评估心功能。关键代谢组织的组织病理学分析(肝脏,肾,和心脏组织)进行。蛋白质印迹或qRT-PCR评估了与炎症相关的关键蛋白质和基因,线粒体,和脂肪组织中的脂质代谢。
结果:与正常饮食的小鼠相比,那些在HFD表现出显著增加的体重和脂肪量。值得注意的是,Sesn2KO进一步加剧了肥胖,展示了最明显的代谢异常:体重增加,脂肪量,糖耐量受损,和胰岛素敏感性,游离脂肪酸和甘油三酯水平升高。此外,KO-HFD小鼠表现出加重的多组织损伤,包括肝酶升高,尿白蛋白排泄增加,心脏功能受损,和脂质在肝脏中的积累,肾,和心脏。此外,脂肪组织显示改变脂质动力学和功能,其特征在于增强的甘油三酯分解和修饰的脂肪因子水平。褐变减少了,KO-HFD小鼠的Pgc1α和Sirt1降低。
结论:Sesn2KO加重了HFD诱导的雌性小鼠肥胖和代谢紊乱。这些发现强调了Sestrin2作为雌性小鼠肥胖调节剂的新作用。
BACKGROUND: Obesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males.
Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice.
METHODS: Female mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues.
RESULTS: In comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice.
CONCLUSIONS: Sesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore
Sestrin2\'s novel role as a regulator of obesity in female mice.