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

Abstract

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 vivo^3,4,5. 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.