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

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.

Effects of dietary methionine and cysteine restriction on plasma biomarkers, serum fibroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study

“…The findings on adipose tissue mRNA expression of DGAT1 and ACAC as well as SCD1 activity indices in plasma became more pronounced when we excluded one outlier with high HOMA-IR at baseline. The increases in serum FGF21 in the Met/Cys -low group is in line with preclinical studies showing upregulated hepatic gene expression and elevated circulating FGF21 in response to methionine restriction [14,18,39]. The range of serum FGF21 concentrations was wide and may have introduced some bias in our analyses, however, our findings also agree with a human study (n = 72) that showed increased plasma FGF21 concentrations in vegans and vegetarians compared with omnivores, and that plasma FGF21 concentrations increased significantly in omnivore subjects (n = 16) given a vegetarian diet for 4 d [40].…”

“…One of the primary biological responses includes effects on lipid metabolism such as increased expression of genes involved in de novo lipogenesis, lipolysis and fatty acid oxidation in liver and white adipose tissue [13,16,17]. The available literature from preclinical work support that fibroblast growth factor 21 (FGF21), a member of the endocrine FGF superfamily, is one of the main factors that regulate lipid and glucose metabolism in methionine restricted mice [18][19][20].…”

“…The primary aim of this pilot study was to evaluate the potential effects of a 7-day diet low, moderate or high in methionine and cysteine content on a wide selection of potential outcomes identified in preclinical and observational studies [9,13,14,16,18] that may aid in the planning and design of a future large-scale study. Outcome measures included plasma lipids, amino acids, glucose, serum FGF21, and other biomarkers related to energy metabolism, including adipose tissue gene expression and plasma SCD activity indices in healthy women with overweight and obesity.…”

Methionine Restriction and Cancer Biology

“…Since some studies have shown that MR activates the integrated stress response [80] (a potentially detrimental action), recent studies have been undertaken to determine if blocking the ability of MR to activate the integrated stress response will enhance its efficacy in treating TNBC [94]. MR has been shown to activate two kinases involved in initiating the integrated stress response: general control nonderepressible 2 (GCN2) and protein kinase R-like endoplasmic reticulum kinase (PERK) [16].…”

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

“…Nonetheless, it is known that certain EAA can be synthesised/spared by metabolism of precursors that can be mobilised within the body and/or supplied by diet 50 , and thus we propose that it is the strictly metabolically EAA, namely Lys, Thr and Trp, which will most likely be limiting in nearly all foodstuffs. In support of this contention, systemic responses to restriction of the EAA Met can be alleviated by dietary Cys-driven methionine sparing [62][63][64] and liver refurbishment of de novo biosynthesis of Thr abated the effects of dietary Thr restriction (Fig 7). In any case, further studies are required to carefully dissect which EAA drive (mal)-adaptive processes during DPD, and in particular which do so under circumstances of altered somatic AA metabolism such as age-related disease, infection, or pregnancy.…”