Unraveling cysteine deficiency-associated rapid weight loss [liver]

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, a-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. Overall design: Various tissues were collected from either WT or cse KO mice kept on different diets and total RNA was isolated by trizol method.

美国人口的40%以及全球每6人中就有1人存在肥胖问题，且全球肥胖发病率正急剧上升[1,2]。为应对这一公共卫生流行病，学界已探索了多种饮食干预手段，包括碳水化合物、脂肪限制，以及近年兴起的氨基酸限制策略[3-6]。本研究探讨了移除单一氨基酸对小鼠体重表型的影响。研究结果显示，与其他必需氨基酸限制方案相比，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%，且该体重变化可被快速逆转。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，二者可形成相互放大的效应，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的产生机制[7-9]。令人意外的是，本研究观察到组织辅酶A（CoA）水平降低——此前学界认为辅酶A的稳定性极强[10]，这一变化会导致线粒体功能受损以及代谢重编程。其最终会引发能量效率低下的无氧糖酵解以及三羧酸（TCA）循环功能障碍，同时伴随丙酮酸、乳清酸、柠檬酸、α-酮戊二酸、富氮化合物以及氨基酸的持续尿液排泄。综上，与其他氨基酸限制方案相比，半胱氨酸限制通过耗尽谷胱甘肽（GSH）与辅酶A，对体重下降、代谢以及应激信号通路产生了最为显著的影响。上述研究结果为应对一系列代谢性疾病以及日益严峻的肥胖危机提供了全新的干预策略。实验整体设计：分别从饲喂不同日粮的野生型（WT）或cse KO小鼠中采集多种组织样本，并通过Trizol法提取总RNA。