Intra-myocellular fatty acid synthesis and breakdown plays a critical role in mediating responses to dietary restriction in Drosophila melanogaster
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE37537 | GEO | 2012/06/15
SECONDARY ACCESSION(S): PRJNA161529
REPOSITORIES: GEO
Similar Datasets
Project description:Dietary restriction (DR) is a robust environmental intervention that slows aging in various species. Changes in fat content have been associated with DR, but whether they play a causal role in mediating various responses to DR remains unknown. We demonstrate that upon DR, Drosophila melanogaster shift their metabolism towards increasing both fatty acid synthesis and breakdown. Inhibition of acetyl CoA carboxylase (ACC), a critical enzyme in fatty acid synthesis, or fatty acid oxidation genes specifically in the muscle tissue inhibited the lifespan extension observed upon DR, suggesting a critical role for intra-myocellular fatty acid metabolism. DR enhances spontaneous activity of flies which was found to be dependent on the enhanced fatty acid metabolism. Furthermore, this increase in activity upon DR was found to partially mediate the lifespan extension upon DR. Over-expression of adipokinetic hormone (dAKH) in whole flies, which increases fat metabolism, led to an increase in spontaneous activity and lifespan in a nutrient dependent manner. Together these results suggest that in Drosophila melanogaster enhanced fat metabolism in the muscle is a key metabolic adaptation in response to DR. 24 experimental samples were analyzed using Nimblegen oligo microarrays. Wild type samples (AL without RU486) were used as the Cy3 reference/control for all experimetal comparisons.
2012-06-14 | E-GEOD-37537 | biostudies-arrayexpress
Project description:Dietary restriction (DR) has been shown to increase lifespan in organisms ranging from yeast to mammals. This suggests that the underlying mechanisms may be evolutionarily conserved. Indeed, upstream signalling pathways, such as TOR, are strongly linked to DR-induced longevity in various organisms. However, the downstream effector proteins that ultimately mediate lifespan extension are less clear. To shed light on this, we used a proteomic approach on budding yeast. Our reasoning was that analysis of proteome-wide changes in response to DR might enable the identification of proteins that mediate its physiological effects, including lifespan extension. Of over 2500 proteins we identified by liquid chromatography-mass spectrometry, 183 were significantly altered in expression by at least 3-fold in response to DR. Most of these proteins were mitochondrial and/or had clear links to respiration and metabolism. Indeed, direct analysis of oxygen consumption confirmed that mitochondrial respiration was increased several-fold in response to DR. In addition, several key proteins involved in mating, including Ste2 and Ste6, were downregulated by DR. Consistent with this, shmoo formation in response to α-factor pheromone was reduced by DR, thus confirming the inhibitory effect of DR on yeast mating. Finally, we found that Hsp26, a member of the conserved small heat shock protein (sHSP) family, was upregulated by DR and that overexpression of Hsp26 extends yeast replicative lifespan. As overexpression of sHSPs in C. elegans and Drosophila has previously been shown to extend lifespan, our data on yeast Hsp26 suggest that sHSPs may be universally conserved effectors of longevity.
2022-02-17 | PXD025004 | Pride
Project description:Primary bile acids are produced in the liver whereas secondary bile acids such as lithocholic acid (LCA) are generated by gut bacteria from primary bile acids that escape the ileal absorption. Besides their well-known function as detergents in lipid digestion, bile acids are important signaling molecules mediating effects on the host’s metabolism. As energy metabolism is closely linked to aging and longevity we supplemented fruit flies (Drosophila melanogaster) with 50 µmol/l LCA either for 30 days or throughout their lifetime. LCA supplementation resulted in a significant induction of the mean (+12 days), median (+10 days) and maximum lifespan (+ 11 days) in comparison to untreated control flies. This lifespan extension was accompanied by an induction of spargel (srl), the fly homolog of mammalian PPARG co-activator 1a(PGC1A. In srl mutant flies, LCA failed to induce longevity emphasizing the essential role of srl in the observed lifespan extension. In addition, the administration of antibiotics to wild type flies abrogated LCA-mediated effects on both lifespan and srl expression, suggesting a substantial contribution of the intestinal microbiota to the LCA-induced longevity. In the present study, we show that the secondary bile acid LCA significantly induced the mean, the median and the maximum survival in Drosophila melanogaster. Our data suggest that besides an up-regulation of the PGC1a-homolog srl unidentified alterations in the structure or metabolism of gut microbiota contribute to the longevity effect of LCA.
2018-08-03 | GSE110367 | GEO
Project description:Dietary restriction (DR) is a robust intervention to slow aging, but how individual tissues respond to DR is largely unknown. We developed a translating ribosome affinity purification method in Drosophila (Fly-TRAP) and investigated mRNA translational profiles of seven primary tissues upon DR. Here we demonstrate that DR alters the mRNA translation expression of proteins genes involved in tissue structural integrity, metabolism, and signal communication in a tissue-specific and coordinated manner. DR enhances the expression of mitochondrial genes in some tissues but decreases in others. Genes involved in mRNA translation were increased specifically in the gut and fat body. A key finding from the study was that DR upregulates several neuroendocrine factors and their corresponding receptors in specific peripheral tissues. Additionally, several a list of secreted factors was in non-neuronal tissues were increased upon changed in response to DR, some of which affected longevity. These results suggest that DR enhances tissue-tissue communication to leading to a longer lifespan and improved tissue homeostasis.
2018-05-20 | GSE81425 | GEO
Project description:Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic JAK-STAT activation, reduced insulin sensitivity and hyperglycaemia, and a shorter lifespan. Drosophila macrophages scavenged lipids and produced the type 1 cytokine upd3, in a scavenger-receptor (croquemort) and JNK-dependent manner. Genetic depletion of macrophages, or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-M-NM-:B signalling made no contribution to the phenotype observed. These results identify an evolutionarily conserved M-bM-^@M-^Xscavenger receptor-JNK-Type 1 cytokineM-bM-^@M-^Y cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic JAK-STAT activation, reduced insulin sensitivity and hyperglycaemia, and a shorter lifespan. Drosophila macrophages scavenged lipids and produced the type 1 cytokine upd3, in a scavenger-receptor (croquemort) and JNK-dependent manner. Genetic depletion of macrophages, or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-M-NM-:B signalling made no contribution to the phenotype observed. These results identify an evolutionarily conserved M-bM-^@M-^Xscavenger receptor-JNK-Type 1 cytokineM-bM-^@M-^Y cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway 5 biological samples were FACS-sorted from different batches of Drosophila melanogaster males after 30 days on 15% lipid enriched diet (n=5) and control diet (n=5)
2015-01-30 | E-GEOD-63254 | biostudies-arrayexpress
Project description:The impact of chronic caloric restriction (CR) on health and survival in model organisms is complex and its underlying molecular mechanisms are poorly understood. Genetic background, sex, degree of CR and diet composition are expected modifiers of survival outcomes of this intervention. A recent study in mice addressed the impact of diet composition and feeding patterns used in nonhuman primates. It was found that, while diet composition alone did not impact longevity, fasting and calories were determinant for increased survival. We use here a combined physiological, multi-omics (transcriptomics-metabolomics), and integrated pathway analyses to gain insight into core and specific pathways associated with liver healthspan and lifespan. Main findings show that liver longevity pathways associated with CR predominantly correspond to detoxification, molecular turnover-repair-maintenance, and energy supply processes. Differential responses on lifespan extension provided by the different feeding strategies unveiled a distinct pattern of longevity pathways that centered around amino acid, fatty acid and nucleic acid metabolisms. Glycine-serine-threonine metabolism was a unique metabolic hub associated with lifespan whereas short-chain fatty acids and essential PUFAs metabolism were unique to healthspan. Nonhuman primate serum metabolomics data essentially recapitulated key features in mice.
2020-07-13 | GSE124294 | GEO
Project description:Pharmacological interventions directly modulating ageing would extend human healthspan, resulting in dramatic medical and economic benefits. Such interventions should be efficacious in adults and ideally repurpose drugs known to be safe. Here we show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved ageing pathways using drugs already used in humans. Using this approach in C. elegans, we were able to slow ageing, improve healthspan and minimize trade-offs. We show that daf-2, daf-7 and sbp-1 (mammalian SREBP-1c) interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and lifespan extension. For one combination, we observed evolutionary conservation in fruit flies. To the best of our knowledge, this is the largest lifespan effect ever reported for any adult-onset drug treatment in C. elegans. Drug repurposing approaches, by leveraging drugs already approved for humans, could lead to rapid translation of experimental results to clinical applications.
2018-12-17 | GSE108263 | GEO
Project description:The nutrient-sensing Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved regulator of longevity. S6 kinase (S6K) is an essential downstream mediator for the effect of TORC1 on longevity. However, mechanistic insights on how TORC1-S6K signalling promotes lifespan and healthspan are still limited. Here we show that activity of S6K in the Drosophila fat body is essential for rapamycin-mediated longevity. Fat-body-specific activation of S6K blocked lifespan extension upon rapamycin feeding and induced accumulation of multilamellar lysosomal enlargements. Besides, fat body-specific S6K knockdown extended lifespan in files. We performed proteomics for Drosophila fat body to explore the fat body-specific regulation of protein expression by two separate datasets: fat body-specific S6K activation (Lsp2GS>S6KCA) with rapamycin treatment; and fat body-specific S6K inhibition (Lsp2GS>S6KRNAi). To assess if the age-prolonging mechanisms of TORC1-S6K signalling are conserved between flies and mammals, we assessed the impact of rapamycin treatment in the proteome of liver from C3B6F1 mice (F1 hybrids of C3H/HeOuJ females and C57Bl/6N males).
2024-01-12 | PXD035293 | Pride
Project description:Expression data from four different lifespan-extending conditions: dietary restriction in two different genetic backgrounds (canton-s and a yw, w1118 combination), sir2 overexpression and p53 knockdown (+/-). Comparison of significantly over and under-expressed genes reveals a signature for dietary restriction and lifespan extension. Abstract A major challenge in translating the positive effects of dietary restriction (DR) for the improvement of human health is the development of therapeutic mimics. One approach to finding DR mimics is based upon identification of the proximal effectors of DR life span extension. Whole genome profiling of DR in Drosophila shows a large number of changes in gene expression, making it difficult to establish which changes are involved in life span determination as opposed to other unrelated physiological changes. We used comparative whole genome expression profiling to discover genes whose change in expression is shared between DR and two molecular genetic life span extending interventions related to DR, increased dSir2 and decreased Dmp53 activity. We find twenty-one genes shared among the three related life span extending interventions. One of these genes, takeout, thought to be involved in circadian rhythms, feeding behavior and juvenile hormone binding is also increased in four other life span extending conditions: Rpd3, Indy, chico and methuselah. We demonstrate takeout is involved in longevity determination by specifically increasing adult takeout expression and extending life span. These studies demonstrate the power of comparative whole genome transcriptional profiling for identifying specific downstream elements of the DR life span extending pathway. 42 samples were used in the analysis. Sir2 overexpression flies and the yw, w1118 background DR flies had the same control. Flies were collected at ages 10 and 40 days. Tissue is whole body females.
2011-01-20 | E-GEOD-26726 | biostudies-arrayexpress
Project description:Expression data from four different lifespan-extending conditions: dietary restriction in two different genetic backgrounds (canton-s and a yw, w1118 combination), sir2 overexpression and p53 knockdown (+/-). Comparison of significantly over and under-expressed genes reveals a signature for dietary restriction and lifespan extension. Abstract A major challenge in translating the positive effects of dietary restriction (DR) for the improvement of human health is the development of therapeutic mimics. One approach to finding DR mimics is based upon identification of the proximal effectors of DR life span extension. Whole genome profiling of DR in Drosophila shows a large number of changes in gene expression, making it difficult to establish which changes are involved in life span determination as opposed to other unrelated physiological changes. We used comparative whole genome expression profiling to discover genes whose change in expression is shared between DR and two molecular genetic life span extending interventions related to DR, increased dSir2 and decreased Dmp53 activity. We find twenty-one genes shared among the three related life span extending interventions. One of these genes, takeout, thought to be involved in circadian rhythms, feeding behavior and juvenile hormone binding is also increased in four other life span extending conditions: Rpd3, Indy, chico and methuselah. We demonstrate takeout is involved in longevity determination by specifically increasing adult takeout expression and extending life span. These studies demonstrate the power of comparative whole genome transcriptional profiling for identifying specific downstream elements of the DR life span extending pathway.
2011-01-20 | GSE26726 | GEO