The role of GCN2 kinase in amino acid dependent longevity and feeding behaviour in Drosophila
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE203210 | GEO | 2022/06/03
REPOSITORIES: GEO
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Project description:Dietary protein dilution (DPD) promotes metabolic remodelling and health but the precise nutritional components driving this response remain elusive. Here we demonstrate that dietary amino acids (AA) are sufficient and necessary to drive the response to DPD. In particular, the restriction of dietary essential AA (EAA) supply, but not non-EAA, drives the systemic metabolic response to total AA deprivation. Furthermore, systemic deprivation of Thr and Trp, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Thr is also potentially limiting in low-protein diet fed humans, and dietary Thr restriction (DTR) retarded the development of obesity-associated metabolic dysfunction in mice. Liver-derived fibroblast growth factor 21 was required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of Thr biosynthetic capacity reversed the systemic response to DTR. Taken together, our studies demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.
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2006-04-03 | E-TABM-85 | biostudies-arrayexpress
Project description:GCN2 (General Control Nonderepressible 2) is a serine/threonine-protein kinase that controls mRNA translation in response to amino acid availability. Here we show that production and clearance of erythrocytes are controlled by GCN2. Our data highlight the importance of tissue-resident macrophages as the primary cell type mediating this effect. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia, GCN2 knockout (GCN2-/-) mice displayed resistance to anemia as compared to wild-type (GCN2+/+) mice. GCN2-/- liver macrophages display defective erythrophagocytosis and lysosome maturation. Molecular analysis of GCN2-/- cells indicates that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating RBC clearance and iron recycling. We performed NRF2 (Nfe2l2) ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation.
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Project description:Non-shivering thermogenesis in the brown adipose tissue (BAT) of rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. Therefore, it is critical to identify signaling pathways which aid in nutrient delivery within this thermogenic tissue.To understand the contribution of the integrated stress response (ISR) in directing adaptive thermogenesis, we examined the role of the kinase activity of general control nonderepressible 2 (GCN2) within the BAT during acute cold exposure. We hypothesized that under hypothermic conditions, GCN2 maintains thermogenesis via ISR gene targets such as fibroblast growth factor 21 (FGF21), that triggers thermogenic uncoupling in BAT. In alignment with our hypothesis, both female and male mice either lacking GCN2 or administered a small molecule inhibitor of GCN2 were profoundly intolerant to acute cold stress. However, while GCN2 deletion in male mice impeded liver-derived FGF21 expression, it did not affect FGF21 levels in females, suggesting an alternative role for GCN2 in the maintenance of thermogenesis. Within the BAT, acute cold exposure increased ISR target genes and thermogenic genes regardless of GCN2 status and sex. RNA sequencing in BAT during cold exposure revealed a gene signature that identified actomyosin mechanics and transmembrane transport as the top two processes requiring GCN2. The top gene signature included cytoskeletal and class II myosin heavy chain genes critical for maximal thermogenesis during cold stress. The second gene signature included amino acid transporters which corresponded with higher circulating amino acids. In conclusion, we identify a novel role for GCN2 activation during acute cold exposure to facilitate mechanosensitive cell signaling and use of amino acids for adaptive thermogenesis.
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Project description:Forty percent of the US population and 1 in 6 individuals worldwide are obese, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and more recently amino acid restriction, have been explored to combat this epidemic3-6. We investigated the impact of removing individual amino acids on the weight profiles of mice. Here, we show that conditional cysteine restriction resulted in the most dramatic weight loss when compared to essential amino acid restriction, amounting to 30% within one week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, which partly explained the phenotype7-9. Surprisingly, we observed lower tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds, and amino acids In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings suggest novel strategies for addressing a range of metabolic diseases and the growing obesity crisis.
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Project description:Forty percent of the US population and 1 in 6 individuals worldwide are obese, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and more recently amino acid restriction, have been explored to combat this epidemic3-6. We investigated the impact of removing individual amino acids on the weight profiles of mice. Here, we show that conditional cysteine restriction resulted in the most dramatic weight loss when compared to essential amino acid restriction, amounting to 30% within one week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, which partly explained the phenotype7-9. Surprisingly, we observed lower tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds, and amino acids In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings suggest novel strategies for addressing a range of metabolic diseases and the growing obesity crisis.
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Project description:Forty percent of the US population and 1 in 6 individuals worldwide are obese, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and more recently amino acid restriction, have been explored to combat this epidemic3-6. We investigated the impact of removing individual amino acids on the weight profiles of mice. Here, we show that conditional cysteine restriction resulted in the most dramatic weight loss when compared to essential amino acid restriction, amounting to 30% within one week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, which partly explained the phenotype7-9. Surprisingly, we observed lower tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds, and amino acids In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings suggest novel strategies for addressing a range of metabolic diseases and the growing obesity crisis.
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