Dietary Sulfur Amino Acid Restriction and the Integrated Stress Response: Mechanistic Insights.

William O Jonsson,Nicholas S Margolies,Tracy G Anthony

doi:10.3390/nu11061349

William O Jonsson, Nicholas S Margolies + Show 1 more

Open Access

https://doi.org/10.3390/nu11061349

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Journal: Nutrients	Publication Date: Jun 15, 2019
Citations: 28	License type: CC BY 4.0

Affiliation: Rutgers, The State University of New Jersey

Abstract

Dietary sulfur amino acid restriction, also referred to as methionine restriction, increases food intake and energy expenditure and alters body composition in rodents, resulting in improved metabolic health and a longer lifespan. Among the known nutrient-responsive signaling pathways, the evolutionary conserved integrated stress response (ISR) is a lesser-understood candidate in mediating the hormetic effects of dietary sulfur amino acid restriction (SAAR). A key feature of the ISR is the concept that a family of protein kinases phosphorylates eukaryotic initiation factor 2 (eIF2), dampening general protein synthesis to conserve cellular resources. This slowed translation simultaneously allows for preferential translation of genes with special sequence features in the 5′ leader. Among this class of mRNAs is activating transcription factor 4 (ATF4), an orchestrator of transcriptional control during nutrient stress. Several ATF4 gene targets help execute key processes affected by SAAR such as lipid metabolism, the transsulfuration pathway, and antioxidant defenses. Exploration of the canonical ISR demonstrates that eIF2 phosphorylation is not necessary for ATF4-driven changes in the transcriptome during SAAR. Additional research is needed to clarify the regulation of ATF4 and its gene targets during SAAR.

Highlights

Dietary sulfur amino acid restriction, referred to as methionine restriction, increases food intake and energy expenditure and alters body composition in rodents, resulting in improved metabolic health and a longer lifespan
Methionine restriction may be more accurately described as sulfur amino acid (SAA) restriction (SAAR)
It was found that hepatic Atf4 expression was elevated in mice after two days of feeding an SAA restricted diet even though levels of eukaryotic initiation factor 2 (eIF2) phosphorylation and GDP/GTP exchange rates on eIF2 were unchanged relative to animals fed a control diet. These results indicate an uncoupling between eIF2 phosphorylation and activating transcription factor 4 (ATF4) synthesis in liver [44]

Summary

The Integrated Stress Response and Detection of Amino Acid Insufficiency

Throughout evolution, all living organisms have encountered periods of nutrient scarcity. This finding differs from that reported in Gcn deleted mice fed a leucine-devoid diet which showed sustained liver protein synthesis at the expense of muscle mass and greater body weight loss as compared to intact mice [46] These differences may be a function of the timing of the measurement, choice of amino acid deprivation or age of the mice, or the combination of these factors. The early uncoupling between eIF2 phosphorylation and ATF4 target gene expression in response to SAAR suggests the presence of a non-canonical ISR; in other words, other post-transcriptional mechanisms may regulate ATF4 levels in vivo, such as altered protein stability. Mice lacking Gcn globally responded to acute SAAR by inducing hepatic Fgf transcript abundancy without increased phosphorylation of eIF2 nor reduced activity of eIF2B in liver [44]. In revealing the precise mechanisms behind the upstream control of FGF21 during SAAR, future efforts will need to consider the relationships between the ISR and other nutrient responsive signaling networks

Altered Feeding Behavior in Response to Sulfur Amino Acid Restriction

Findings

Perspectives