Dietary sulfur amino acid restriction improves metabolic health by reducing fat mass

Diet interventions such as calorie restriction or time-restricted feeding offer potential for weight management, but long-term success is often hindered by poor adherence due to the rewarding effects of sugars. In this study, we demonstrate that sulfur amino acid restriction (SAAR) diets promote rapid fat loss without impairing appetite and physiological locomotion, outperforming diets with restricted branched-chain amino acids. Weekly cycling of SAAR diets preserves metabolic benefits, such as reduced fat mass and improved glucose sensitivity. Metabolic analysis and <i>in vivo</i> isotope tracing revealed a shift toward carbohydrate oxidation in white and brown adipose tissue (WAT and BAT), and liver during the SAAR diet refeeding state, leading to decreased <i>de novo</i> lipogenesis. Enhanced lipolysis and fatty acid oxidation were observed in the heart, brain, BAT, lungs, etc. The reintroduction of methionine or cystine negated these metabolic benefits. Further ¹³C and ²H tracing experiments indicated that cystine, rather than its derivatives like taurine or H₂S, directly regulates adiposity. In a high-fat diet model, SAAR diet led to sustained fat mass reduction, regardless of the timing of intervention. Additionally, cystine levels correlated positively with body mass index (BMI) and total triglycerides in diabetic patients. Our findings highlight SAAR diet as a promising strategy for long-term weight control by modulating systemic glucose and lipid metabolism homeostasis.