Unravelling cysteine-deficiency-associated rapid weight loss

Alan Varghese, Ivan Gusarov, Begoña Gamallo-Lana, Daria Dolgonos, Yatin Mankan, Ilya Shamovsky, Mydia Phan, Rebecca Jones, Maria Gomez-Jenkins, Eileen White, Rui Wang, Drew R. Jones, Thales Papagiannakopoulos, Michael E. Pacold, Adam C. Mar, Dan R. Littman () and Evgeny Nudler ()
Additional contact information
Alan Varghese: NYU Grossman School of Medicine
Ivan Gusarov: NYU Grossman School of Medicine
Begoña Gamallo-Lana: NYU Grossman School of Medicine
Daria Dolgonos: NYU Grossman School of Medicine
Yatin Mankan: NYU Grossman School of Medicine
Ilya Shamovsky: NYU Grossman School of Medicine
Mydia Phan: NYU Grossman School of Medicine
Rebecca Jones: NYU Grossman School of Medicine
Maria Gomez-Jenkins: Rutgers University
Eileen White: Rutgers University
Rui Wang: York University
Drew R. Jones: NYU Grossman School of Medicine
Thales Papagiannakopoulos: NYU Langone Health
Michael E. Pacold: NYU Langone Health
Adam C. Mar: NYU Grossman School of Medicine
Dan R. Littman: NYU Grossman School of Medicine
Evgeny Nudler: NYU Grossman School of Medicine

Nature, 2025, vol. 643, issue 8072, 776-784

Abstract: 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 epidemic3–6. 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 1 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, partly explaining the phenotype7–9. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08996-y

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