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Redox-dependent pathways in the pro-thermogenic effects of cysteine restriction

Nature Metabolism (2025)Cite this article

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In their recent article, Lee et al.1 elegantly demonstrate that dietary cysteine restriction induces rapid weight loss and adipose tissue remodelling via a sympathetic nervous system pathway that is independent of UCP1. At the same time, Varghese et al.2 report that the same dietary constraint ignites a robust thermogenic programme, with loss of fat mass and activation of the integrated stress response. Notably, circulating GDF15 and FGF21 amplify, but are not indispensable for, the phenotype, which persists — albeit attenuated — in Gdf15 and Fgf21-knock-out mice. A marked fall in the cysteine-containing antioxidant glutathione (GSH) in liver and adipose tissue underscores redox imbalance as an early event. Together, the two studies highlight the translational potential of cysteine restriction as a weight loss intervention, yet leave open key questions on the redox mechanisms within adipocytes that couple cysteine availability to thermogenic output.

Depletion of GSH has been shown to reduce adiposity and is sufficient to improve insulin sensitivity as well as induce thermogenesis in adipocytes and in vivo3,4,5. Our laboratory demonstrated that pharmacological inhibition of γ-glutamylcysteine ligase with buthionine sulfoximine lowers GSH, boosts mitochondrial reactive oxygen species (mtROS) and activates the redox-sensitive transcription factor FOXO1, thereby inducing Ucp1 and Ppargc1a in adipocytes5. The gene program triggered in cultured adipocytes mirrors the in vivo response, demonstrating that adipocytes themselves are sufficient redox sensors independent of systemic inputs. These effects were reversed by cysteine supplementation, arguing that the local redox status of adipose tissue constitutes a gatekeeper for thermogenic activation.

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Fig. 1: Cysteine scarcity drives adipocyte thermogenesis.

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Acknowledgements

This work was partially supported by the European Union – Next Generation EU, under the codes PRIN 2022 (Prot. 2022Z9HYJH) and PRIN 2022 PNRR (Prot. P2022LS3FF) to D.L.-B., and by the MUR–PNRR M4C2 I1.3 PE6 project PE00000019 ‘HEAL Italia’ to K.A.

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  1. Department of Biology, University of Rome Tor Vergata, Rome, Italy

    Daniele Lettieri-Barbato & Katia Aquilano

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  1. Daniele Lettieri-Barbato
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  2. Katia Aquilano
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D.L.-B. and K.A. equally conceived, wrote and edited the manuscript.

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Correspondence to Daniele Lettieri-Barbato or Katia Aquilano.

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The authors declare no competing interests.

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Lettieri-Barbato, D., Aquilano, K. Redox-dependent pathways in the pro-thermogenic effects of cysteine restriction. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01384-w

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