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Cited by 45Adipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic DiseasesLipid metabolism and biosynthesis

Cysteine depletion triggers adipose tissue thermogenesis and weight loss

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Lee, Aileen H., Orliaguet, Lucie, Youm, Yun-Hee, Maeda, Rae, Dlugos, Tamara, Lei, Yuanjiu, Coman, Daniel, Shchukina, Irina +11 more·2025·Nature Metabolism
DOI 10.1038/s42255-025-01297-8PMC PMC12198010

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Abstract

Abstract Dietary interventions such as caloric restriction (CR) 1 and methionine restriction 2 that prolong lifespan induce the ‘browning’ of white adipose tissue (WAT), an adaptive metabolic response that increases heat production to maintain health 3,4 . However, how diet influences adipose browning and metabolic health is unclear. Here, we identified that weight-loss induced by CR in humans 5 reduces cysteine concentration in WAT suggesting depletion of this amino-acid may be involved in metabolic benefits of CR. To investigate the role of cysteine on organismal metabolism, we created a cysteine-deficiency mouse model in which dietary cysteine was eliminated and cystathionine γ-lyase (CTH) 6 , the enzyme that synthesizes cysteine was conditionally deleted. Using this animal model, we found that systemic cysteine-depletion causes drastic weight-loss with increased fat utilization and browning of adipose tissue. The restoration of dietary cysteine in cysteine-deficient mice rescued weight loss together with reversal of adipose browning and increased food-intake in an on-demand fashion. Mechanistically, cysteine deficiency induced browning and weight loss is dependent on sympathetic nervous system derived noradrenaline signaling via β3-adrenergic-receptors and does not require UCP1. Therapeutically, in high-fat diet fed obese mice, one week of cysteine-deficiency caused 30% weight-loss and reversed inflammation. These findings thus establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.

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  • Multiple longevity interventions in rodents are associated with rewiring of the transsulfuration pathway that feeds into taurine synthesis.

    “Multiple longevity interventions in rodents have been associated with the rewiring of the TSP that feeds into taurine synthesis.34–38”

    From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [38]

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Cited by

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Authors
Lee, A. H., Orliaguet, L., Youm, Y.-H., Maeda, R., Dlugos, T., Lei, Y., Coman, D., Shchukina, I., Andhey, P. S., Smith, S. R., Ravussin, E., Stadler, K., Chen, B., Artyomov, M. N., Hyder, F., Horvath, T. L., Schneeberger, M., Sugiura, Y., & Dixit, V. D.
Affiliations
  • Yale University (US)
  • Kyoto University (JP)
  • Washington University in St. Louis (US)
  • AdventHealth Orlando (US)
Corresponding author
Dixit, Vishwa Deep
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2025-06-03
Volume
7
Issue
6
Pages
1204-1222
ISSN
2522-5812 (ISSN-L)
DOI
10.1038/s42255-025-01297-8
PMC
PMC12198010
OpenAlex
W4410973905
Cited by
45
References
11
Citations by year
2026: 22 · 2025: 23
FWCI
28.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Metabolism (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG031797, AG073969, AG068863, P01AG051459)
  • U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R00DK1208689)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
cysteine depletion, white adipose tissue browning, thermogenesis, weight loss, caloric restriction, methionine restriction, beta3-adrenergic receptor, energy expenditure, metabolic inflammation, obesity, sulfur-containing amino acids, thiol metabolism

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