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Nutritional geometry framework on sleep in Drosophila

ABSTRACT: Sleep is a fundamental physiological function and is essential for all animals, including humans. Sleep has been reported to be affected by diet compositions including protein (P) and carbohydrates (C), but there has not been a systematic investigation of the effect of dietary macronutrient balance on sleep. Here, we used the nutritional geometry framework (NGF) to explore the interactive effects on sleep of protein (P) and carbohydrate (C) in the model organism Drosophila. Our results showed that the combination of low protein and moderate carbohydrate prolonged sleep time and sleep quality, with fewer sleep episodes and longer sleep duration. We further found that the effects of macronutrients on sleep mirrored levels of haemolymph glucose and whole-body glycogen. Moreover, transcriptome analyses revealed that high protein, low carbohydrate diet elevated the gene expression of amino acid metabolic pathways when compared to a diet lacking protein, with the glycine, serine, threonine metabolism pathway being most strongly regulated. However, sleep was not decreased in flies fed on a protein-deficient diet with added glycine, serine and threonine. In summary, our results demonstrate that sleep is affected by the balance of protein and carbohydrates in the diet and that reduced protein coupled with moderate carbohydrate promote sleep duration and quality.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE188430 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:Short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (e.g., genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of short habitual sleep duration on gene expression. Therefore, we sought to investigate gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD=18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with two-weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Next, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. The mean 24 hour sleep duration of the total sample was 439.2 minutes (SD=46.8 minutes; range 325.4 to 521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD=21.2; range 45.9 to 114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular and inflammatory outcomes.

Project description:N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2), recognize N-terminal (Nt) glycine degrons and participate in the Nt-myristoylation quality control through the Gly/N-degron pathway. Here we show that ZER1 and ZYG11B can also recognize small Nt-residues other than glycine. Specifically, ZER1 preferentially binds to Nt-serine, -alanine, -threonine and -cysteine over -glycine, while ZYG11B prefers Nt-glycine but also has the capacity to recognize Nt-serine, -alanine and -cysteine in vitro. Nt-serine, -alanine and -cysteine undergo Nt-acetylation by NatA, thereby shielding them from recognition by ZER1/ZYG11B in cells. We found that ZER1/ZYG11B is able to target the non-acetylation of small Nt-residue degrons for degradation in NatA-deficient cells, implicating its role in the Nt-acetylation quality control. Furthermore, we present the crystal structures of ZER1 and ZYG11B bound to various small Nt-residues and uncover the molecular mechanism of non-acetylated substrate recognition by ZER1 and ZYG11B.N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2), recognize N-terminal (Nt) glycine degrons and participate in the Nt-myristoylation quality control through the Gly/N-degron pathway. Here we show that ZER1 and ZYG11B can also recognize small Nt-residues other than glycine. Specifically, ZER1 preferentially binds to Nt-serine, -alanine, -threonine and -cysteine over -glycine, while ZYG11B prefers Nt-glycine but also has the capacity to recognize Nt-serine, -alanine and -cysteine in vitro. Nt-serine, -alanine and -cysteine undergo Nt-acetylation by NatA, thereby shielding them from recognition by ZER1/ZYG11B in cells. We found that ZER1/ZYG11B is able to target the non-acetylation of small Nt-residue degrons for degradation in NatA-deficient cells, implicating its role in the Nt-acetylation quality control. Furthermore, we present the crystal structures of ZER1 and ZYG11B bound to various small Nt-residues and uncover the molecular mechanism of non-acetylated substrate recognition by ZER1 and ZYG11B.

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Nutritional geometry framework on sleep in Drosophila

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