Unraveling cysteine deficiency-associated rapid weight loss [muscle]

Forty percent of the US population and 1 in 6 individuals worldwide are obese, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and more recently amino acid restriction, have been explored to combat this epidemic3-6. We investigated the impact of removing individual amino acids on the weight profiles of mice. Here, we show that conditional cysteine restriction resulted in the most dramatic weight loss when compared to essential amino acid restriction, amounting to 30% within one week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, which partly explained the phenotype7-9. Surprisingly, we observed lower tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, -ketoglutarate, nitrogen rich compounds, and amino acids In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings suggest novel strategies for addressing a range of metabolic diseases and the growing obesity crisis. Various tissues were collected from either WT or cse KO mice kept on different diets and total RNA was isolated by trizol method.美国人口中有40%、全球每6人中便有1人罹患肥胖，且全球肥胖发病率呈飙升态势[1,2]。为应对这一公共健康危机，学界已探索多种饮食干预手段，涵盖碳水化合物限制、脂肪限制以及近年兴起的氨基酸限制疗法[3-6]。本研究探究了剔除单一氨基酸对小鼠体重变化特征的影响。结果显示，相较于其他必需氨基酸限制方案，条件性半胱氨酸限制可带来最为显著的体重下降——一周内即可降低30%，且该体重减轻效应可被快速逆转。研究发现，半胱氨酸缺乏会激活整合应激反应（integrated stress response）与氧化应激反应，二者相互增强，进而诱导生长分化因子15（GDF15）和成纤维细胞生长因子21（FGF21）的表达，这在一定程度上解释了上述表型[7-9]。令人意外的是，我们观测到组织内辅酶A（CoA）水平显著降低——此前该物质被认为具有极高的稳定性[10]，这一变化最终导致线粒体功能受损与代谢重编程。上述改变会引发能量利用效率低下的无氧糖酵解以及三羧酸循环（TCA cycle）功能障碍，同时伴随丙酮酸、乳清酸、柠檬酸、α-酮戊二酸、富氮化合物及氨基酸的持续性尿液排泄。综上，本研究表明，相较于其他氨基酸限制方案，半胱氨酸限制通过耗竭谷胱甘肽（GSH）与辅酶A（CoA），对体重减轻、代谢进程及应激信号通路产生了最为显著的调控效应。上述研究结果为应对一系列代谢性疾病与日益严峻的全球肥胖危机提供了全新的干预思路。本研究从接受不同饮食干预的野生型（WT）或胱硫醚γ-裂解酶敲除（cse KO）小鼠体内采集多种组织，并采用Trizol法提取总RNA。