近日，美国细胞生物系教授Evgeny Nudler及其研究组的最新研究解开半胱氨酸缺乏相关的快速减肥。2025年5月21日，国际知名学术期刊《自然》发表了这一成果。

在这里，该课题组研究人员研究了去除单个氨基酸对小鼠体重分布的影响。课题组研究人员发现，与必需氨基酸限制相比，有条件的半胱氨酸限制导致了最显著的体重减轻，在1周内减少了30%，这很容易逆转。该团队发现，半胱氨酸缺乏激活了综合应激反应和氧化应激反应，两者相互放大，导致GDF15和FGF21的诱导，部分解释了表型。值得注意的是，研究组观察到组织辅酶A （CoA）水平较低，这被认为是非常稳定的，导致线粒体功能降低和代谢重新布线。这导致能量效率低下的厌氧糖酵解和缺陷的三羧酸循环，尿中持续排出丙酮酸、羊角酸、柠檬酸、α-酮戊二酸、富氮化合物和氨基酸。总之，他们的研究表明，与其他氨基酸限制相比，通过消耗谷胱甘肽和辅酶a来限制半胱氨酸对体重减轻、代谢和应激信号的影响最大。这些发现为解决一系列代谢疾病和日益严重的肥胖危机提供了策略。

研究人员表示，大约40%的美国人口和全球六分之一的人患有肥胖症，全球发病率正在飙升。已经探索了各种饮食干预措施，包括碳水化合物、脂肪和最近的氨基酸限制，以对抗这种流行病。

附：英文原文

Title: Unravelling cysteine-deficiency-associated rapid weight loss

Author: Varghese, Alan, Gusarov, Ivan, Gamallo-Lana, Begoa, Dolgonos, Daria, Mankan, Yatin, Shamovsky, Ilya, Phan, Mydia, Jones, Rebecca, Gomez-Jenkins, Maria, White, Eileen, Wang, Rui, Jones, Drew R., Papagiannakopoulos, Thales, Pacold, Michael E., Mar, Adam C., Littman, Dan R., Nudler, Evgeny

Issue&Volume: 2025-05-21

Abstract: Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3,4,5,6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1week, 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, partly explaining the phenotype7,8,9. Notably, we observed lower levels of 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 tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-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 signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

DOI: 10.1038/s41586-025-08996-y

Source: https://www.nature.com/articles/s41586-025-08996-y