50.5/Q1，肥胖干预新进展！Nature发纽约大学成果：限硫氨基酸减肥效应可逆

Core Viewpoint - The article discusses the rising global obesity rates and highlights the potential of cysteine-restricted diets as an intervention method, focusing on the molecular mechanisms behind rapid weight loss induced by cysteine limitation [8][9]. Research Background and Purpose - Background: The global obesity prevalence is increasing, and cysteine-restricted diets are gaining attention as a potential intervention method. Cysteine is a crucial precursor for synthesizing glutathione (GSH) and coenzyme A (CoA), but the specific effects of cysteine limitation on body weight and its regulatory mechanisms remain unclear [8]. - Purpose: The study aims to explore the molecular mechanisms behind rapid weight loss induced by cysteine restriction using mouse experiments, providing new targets for obesity treatment [9]. Research Methods - Study Design: The research utilized Cse gene knockout (KO) and wild-type (WT) mice, administering cysteine-restricted diets (no-Cys) and other essential amino acid-restricted diets, combined with metabolic cage monitoring and comprehensive transcriptomic and metabolomic analyses [10]. - Data Sources: The study collected metabolic products from mouse liver, muscle, fat tissues, serum, and urine, with sample sizes ranging from 3 to 9 mice per experimental group [11]. - Research Variables: The focus was on cysteine intake, body weight changes, and metabolic indicators such as GSH, CoA, and inflammatory factors [12]. - Analysis Methods: Techniques included RNA sequencing, LC-MS metabolomics, immunohistochemistry, Western blotting, and indirect energy metabolism measurement [13]. Research Results 1. Cysteine deficiency leads to rapid and reversible weight loss: Cse KO mice on a no-Cys diet experienced a weight loss of up to 30% within one week, significantly exceeding other essential amino acid-restricted groups. Weight returned to baseline upon resuming normal diet, indicating that weight loss was primarily due to cysteine deficiency [14]. 2. Metabolic reprogramming promotes fat consumption and browning: The no-Cys diet reduced the respiratory exchange ratio (RER) and total fat mass, with a notable increase in UCP1-positive cells in white adipose tissue, indicating brown fat characteristics. Liver transcriptomic results showed activation of fatty acid oxidation pathways and suppression of fat synthesis genes [16]. 3. Integration of stress pathways and oxidative stress: Cysteine restriction activated integrated stress response (ISR) and oxidative stress response (OSR), significantly increasing serum levels of GDF15 and FGF21. Deletion of Gdf15 or Fgf21 slowed weight loss, suggesting their roles in metabolic adaptation regulation [19]. 4. CoA reduction leads to decreased metabolic efficiency: The no-Cys diet lowered liver CoA levels, resulting in increased urinary excretion of TCA cycle intermediates, indicating impaired mitochondrial oxidative phosphorylation capacity [20][21]. 5. Tissue-specific regulation of energy metabolism pathways: ISR and OSR-related genes were significantly upregulated in the liver, while muscle primarily activated oxidative stress pathways, and adipose tissue emphasized lipolysis and browning responses, demonstrating coordinated regulation across multiple tissues for systemic metabolic remodeling [23]. Research Conclusion and Limitations - Conclusion: Cysteine restriction promotes rapid weight loss by depleting GSH and CoA, activating stress responses, enhancing fat oxidation, reducing metabolic efficiency, and stimulating creatine cycling compensation. This physiological process is reversible and offers new insights for obesity treatment [27]. - Limitations: The study has not assessed the safety of cysteine restriction in humans, and the long-term effects on other organs and gender differences remain unexplored, necessitating further validation of the underlying mechanisms [28]. Future Research Directions - Future studies should evaluate the weight loss effects and safety of cysteine restriction in primates, analyze the impact of cysteine deficiency on gut microbiota, and explore the molecular mechanisms of gender differences in response to cysteine restriction to advance personalized intervention strategies [29].