Existing data derived from animal models suggest that improvements in metabolic health leading to reductions in adiposity, increases in energy expenditure and even possibly increased life span can be obtained from limiting the consumption of sulfur amino acids (SAAR).  The mechanisms involved in these benefits are not well understood.  As a result, Jonsson and colleagues conducted a study to determine if activating transcription factor 4 (ATF4) serves as a key regulator within the integrated stress response (ISR) induced by SAAR.  The April 2021 issue of The Journal of Nutrition contains a paper describing their observations.

Female and male mice with liver or whole body knockdown of Atf4 were used to determine the role of ATF4 in physiological responses to SAAR.  Observations included open-circuit calorimetry, serum amino acid concentrations, serum FGF21 concentrations, hepatic glutathione concentrations, hepatic hydrogen sulfide production, liver protein and DNA synthesis rates, and liver gene expression.

The induction of hepatokine fibroblast growth factor 21 was not dependent upon ATF4, but ATF4 was needed to support redox homeostasis using the transsulfuration pathway.  In addition, biological sex was a determinant of the physiological responses to SAAR, independent of ATF4 status.  These observations led the authors to suggest that other components of the ISR other than ATF4 are required for the improvement in metabolic health seen with SAAR.

In a commentary on this article, Bruhat and colleagues describe the results reported by Jonsson and colleagues as a substantial increase in the understanding of ISR and gender in the effects of SAAR.  Even though the response to longer term SAAR likely involves several complex mechanisms, studies exploring the responses are needed if the goals of improving metabolic health and reducing disease are to be achieved through dietary interventions.


Jonsson WO, Margolies NS, Mirek ET, Zhang Q, Linden MA, Hill CM et al.  Physiological responses to dietary sulfur amino acid restriction in mice are influenced by Atf4 status and biological sex.  Journal of Nutrition, Volume 151, Issue 4, April 2021, Pages 785–799, https://doi.org/10.1093/jn/nxaa396.

Bruhat A, Papet I, Fafournoux P. Complex mechanisms link dietary sulfur amino acid restriction to health improvement.  Journal of Nutrition, Volume 151, Issue 4, April 2021, Pages 749–750, https://doi.org/10.1093/jn/nxaa457.

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