One in 6 individuals worldwide are obese, and the incidence of this disease is surging globally1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic3-6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, and was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues7. Further analysis demonstrated that this weight reduction primarily stemmed from an increase in the utilization of fat mass for energy production and thermogenesis. Locomotion, circadian rhythm and histological appearance of multiple non-adipose tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, food aversion and energy homeostasis8,9. We additionally observed rapid tissue coenzyme A (CoA) depletion, reducing mitochondrial functionality and leading to metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, mitochondrial metabolism, and stress signaling compared to other amino acid restrictions. Our results also highlight that benefits of sulfur amino acid restriction are primarily driven by cysteine restriction and not methionine restriction. These findings may pave the way to innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.