Thursday, May 22, 2025
No menu items!
HomeNatureUnravelling cysteine-deficiency-associated rapid weight loss

Unravelling cysteine-deficiency-associated rapid weight loss

  • NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387, 1377–1396 (2016).

    Article 

    Google Scholar
     

  • Stierman, B. et al. National Health and Nutrition Examination Survey 2017–March 2020 Prepandemic Data Files—Development of Files and Prevalence Estimates for Selected Health Outcomes National Health Statistics Reports no. 158 (CDC, 2021).

  • Fontana, L. et al. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep. 16, 520–530 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Samaha, F. F. et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N. Engl. J. Med. 348, 2074–2081 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stolt, E. et al. Sulfur amino acid restriction, energy metabolism and obesity: a study protocol of an 8-week randomized controlled dietary intervention with whole foods and amino acid supplements. J. Transl. Med. 19, 153 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yancy, W. S. Jr, Olsen, M. K., Guyton, J. R., Bakst, R. P. & Westman, E. C. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann. Intern. Med. 140, 769–777 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Coll, A. P. et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578, 444–448 (2020).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Fisher, F. M. & Maratos-Flier, E. Understanding the Physiology of FGF21. Annu. Rev. Physiol. 78, 223–241 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Suriben, R. et al. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Nat. Med. 26, 1264–1270 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Smith, C. M., Narrow, C. M., Kendrick, Z. V. & Steffen, C. The effect of pantothenate deficiency in mice on their metabolic response to fast and exercise. Metabolism 36, 115–121 (1987).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rose, W. C. The nutritive significance of the amino acids and certain related compounds. Science 86, 298–300 (1937).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Ishii, I. et al. Cystathionine gamma-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury. J. Biol. Chem. 285, 26358–26368 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mani, S., Yang, G. & Wang, R. A critical life-supporting role for cystathionine gamma-lyase in the absence of dietary cysteine supply. Free Radic. Biol. Med. 50, 1280–1287 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Du, Y., Meng, Q., Zhang, Q. & Guo, F. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT. Amino Acids 43, 725–734 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guo, F. & Cavener, D. R. The GCN2 eIF2α kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab. 5, 103–114 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xiao, F. et al. Effects of essential amino acids on lipid metabolism in mice and humans. J. Mol. Endocrinol. 57, 223–231 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xiao, F. & Guo, F. Impacts of essential amino acids on energy balance. Mol. Metab. 57, 101393 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, X. et al. Dietary tryptophan, tyrosine, and phenylalanine depletion induce reduced food intake and behavioral alterations in mice. Physiol. Behav. 244, 113653 (2022).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Hao, S. et al. Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307, 1776–1778 (2005).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Day, E. A. et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat. Metab. 1, 1202–1208 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kilberg, M. S., Shan, J. & Su, N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol. Metab. 20, 436–443 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, K. H. et al. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation. Biochem. Biophys. Res. Commun. 440, 76–81 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gusarov, I. et al. Dietary thiols accelerate aging of C. elegans. Nat. Commun. 12, 4336 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jonsson, W. O., Margolies, N. S. & Anthony, T. G. Dietary sulfur amino acid restriction and the integrated stress response: mechanistic insights. Nutrients https://doi.org/10.3390/nu11061349 (2019).

  • Miller, R. A. et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119–125 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Richie, J. P. Jr et al. Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J. 8, 1302–1307 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lu, S. C. Glutathione synthesis. Biochim. Biophys. Acta 1830, 3143–3153 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jackowski, S. & Rock, C. O. Regulation of coenzyme A biosynthesis. J. Bacteriol. 148, 926–932 (1981).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leonardi, R., Zhang, Y. M., Rock, C. O. & Jackowski, S. Coenzyme A: back in action. Prog. Lipid Res. 44, 125–153 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Robishaw, J. D., Berkich, D. & Neely, J. R. Rate-limiting step and control of coenzyme A synthesis in cardiac muscle. J. Biol. Chem. 257, 10967–10972 (1982).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, L. et al. Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 117, 2351–2360 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yoneshiro, T. et al. BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature 572, 614–619 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gietzen, D. W. & Aja, S. M. The brain’s response to an essential amino acid-deficient diet and the circuitous route to a better meal. Mol. Neurobiol. 46, 332–348 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fabbiano, S. et al. Caloric restriction leads to browning of white adipose tissue through type 2 immune signaling. Cell Metab. 24, 434–446 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Go, G. W. & Mani, A. Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Yale J. Biol. Med. 85, 19–28 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horton, J. D., Cohen, J. C. & Hobbs, H. H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32, 71–77 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rouland, A. et al. Role of apolipoprotein C1 in lipoprotein metabolism, atherosclerosis and diabetes: a systematic review. Cardiovasc. Diabetol. 21, 272 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, C. H. et al. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J. Biol. Chem. 276, 20858–20865 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kasai, S. et al. Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control. J. Clin. Biochem. Nutr. 64, 1–12 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Copple, I. M. et al. The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system. Hepatology 48, 1292–1301 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Itoh, K. et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13, 76–86 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eisenstein, A. et al. Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs. Immunity 55, 1082–1095 e1085 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Patel, S. et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 29, 707–718 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qi, L. et al. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312, 1763–1766 (2006).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Asantewaa, G. et al. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression. Nat. Commun. 15, 6152 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Naquet, P., Kerr, E. W., Vickers, S. D. & Leonardi, R. Regulation of coenzyme A levels by degradation: the ‘ins and outs’. Prog. Lipid Res. 78, 101028 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Simcox, J. et al. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab. 26, 509–522 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rahbani, J. F. et al. Creatine kinase B controls futile creatine cycling in thermogenic fat. Nature 590, 480–485 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vina, J. et al. The effect of cysteine oxidation on isolated hepatocytes. Biochem. J. 212, 39–44 (1983).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Triguero, A. et al. Liver intracellular l-cysteine concentration is maintained after inhibition of the trans-sulfuration pathway by propargylglycine in rats. Br. J. Nutr. 78, 823–831 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stipanuk, M. H., Dominy, J. E. Jr, Lee, J. I. & Coloso, R. M. Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism. J. Nutr. 136, 1652S–1659S (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bradley, H. et al. Sulfate metabolism is abnormal in patients with rheumatoid arthritis. Confirmation by in vivo biochemical findings. J. Rheumatol. 21, 1192–1196 (1994).

    CAS 
    PubMed 

    Google Scholar
     

  • Elshorbagy, A. K., Valdivia-Garcia, M., Refsum, H. & Butte, N. The association of cysteine with obesity, inflammatory cytokines and insulin resistance in Hispanic children and adolescents. PLoS ONE 7, e44166 (2012).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gordon, C., Bradley, H., Waring, R. H. & Emery, P. Abnormal sulphur oxidation in systemic lupus erythematosus. Lancet 339, 25–26 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heafield, M. T. et al. Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson’s and Alzheimer’s disease. Neurosci. Lett. 110, 216–220 (1990).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ozkan, Y., Ozkan, E. & Simsek, B. Plasma total homocysteine and cysteine levels as cardiovascular risk factors in coronary heart disease. Int. J. Cardiol. 82, 269–277 (2002).

    Article 
    PubMed 

    Google Scholar
     

  • Kiselevsky, Y. V., Ostrovtsova, S. A. & Strumilo, S. A. Kinetic characterization of the pyruvate and oxoglutarate dehydrogenase complexes from human heart. Acta Biochim. Pol. 37, 135–139 (1990).

    CAS 
    PubMed 

    Google Scholar
     

  • Marcel, Y. L. & Suzue, G. Kinetic studies on the specificity of long chain acyl coenzyme A synthetase from rat liver microsomes. J. Biol. Chem. 247, 4433–4436 (1972).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, G., Chen, Z., Hu, Y. & Huang, P. Inhibition of mitochondrial respiration and rapid depletion of mitochondrial glutathione by β-phenethyl isothiocyanate: mechanisms for anti-leukemia activity. Antioxid. Redox Signal. 15, 2911–2921 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, G. et al. Integrated stress response couples mitochondrial protein translation with oxidative stress control. Circulation 144, 1500–1515 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mina, A. I. et al. CalR: a web-based analysis tool for indirect calorimetry experiments. Cell Metab. 28, 656–666 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anders, S., Pyl, P. T. & Huber, W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Banh, R. S. et al. The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway. Nature 597, 420–425 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, W. W., Freinkman, E., Wang, T., Birsoy, K. & Sabatini, D. M. Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell 166, 1324–1337 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Simon-Manso, Y. et al. Metabolite profiling of a NIST Standard Reference Material for human plasma (SRM 1950): GC-MS, LC-MS, NMR, and clinical laboratory analyses, libraries, and web-based resources. Anal. Chem. 85, 11725–11731 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Smith, C. A. et al. METLIN: a metabolite mass spectral database. Ther. Drug monit. 27, 747–751 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Virtanen, P. et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat. Methods 17, 261–272 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments