Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 in mice
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ABSTRACT:
PROVIDER: PRJNA418412 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6292420.fastq.gz | Fastqsanger.gz | |||
| SRR6292430.fastq.gz | Fastqsanger.gz | |||
| SRR6292440.fastq.gz | Fastqsanger.gz | |||
| SRR6292450.fastq.gz | Fastqsanger.gz | |||
| SRR6292421.fastq.gz | Fastqsanger.gz |
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Project description:Dietary restriction (DR) is the most studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of specific genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways can also act to extend lifespan and health span in model organisms. For example, both male and female mice lacking insulin receptor substrate 1 (IRS1) are long-lived and are protected against several age-associated pathologies. However, it remains unclear as to how these particular interventions act mechanistically to produce their beneficial effects, and indeed whether different interventions act through shared or distinct processes. In the following study we investigated multi-tissue transcriptional responses in 15-month-old wild type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL respectively) or fed a 30% DR diet (WTDR or KODR respectively). Using an RNAseq approach we noted little transcriptional overlap between liver, skeletal muscle, brain and white adipose tissue within either WTDR or KOAL mice, but that a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice. Additionally, many metabolic features were similarly shared between WTDR and KOAL mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice, further supporting the notion of mechanistic overlap between these long-lived mouse models. However, there was evidence of disconnect between transcriptional signatures and in certain phenotypic measures between KOAL and KODR, in that additive effects on body mass and body composition were observed but that DR induced a unique set of genes and pathways in these already long-lived mice.
2018-07-18 | GSE106903 | GEO
Project description:Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice.
| S-EPMC5990393 | biostudies-literature
Project description:High energy intake and, specifically, high dietary fat intake challenges the mammalian metabolism and correlates with many metabolic disorders, such as obesity and diabetes. Dietary restriction (DR) is, on the other hand, known to prevent the development of metabolic disorders. The current Western diets are highly enriched in fat and it is as yet unclear whether DR on a certain high-fat (HF) diet elicits similar beneficial effects on health. Here, we report that HF-DR improves metabolic health of mice, compared to mice receiving the same diet on an ad-libitum basis (HF-AL). Already after five weeks of restriction the serum levels of cholesterol and leptin were significantly decreased in HF-DR mice, while their glucose sensitivity and serum adiponectin levels were increased. The body weight and measured serum parameters remained stable in the following 7 weeks of restriction, implying metabolic adaptation. To understand the molecular events associated with this adaptation, we analysed gene expression in white adipose tissue (WAT) with whole genome microarrays. HF-DR strongly influenced gene expression in WAT; in total 8,643 genes were differentially expressed between both groups of mice, with a major role for genes involved in lipid metabolism and mitochondrial functioning. This was confirmed by qRT-PCR and substantiated by an increase in mitochondrial density in WAT of HF-DR mice. These results provide new insights in the metabolic flexibility of dietary restricted animals and suggest the development of substrate efficiency. Limiting food intake by decreasing portion sizes, while maintaining energy sufficiency, may similarly benefit metabolic health in humans.
2011-08-24 | GSE27213 | GEO
Project description:Dietary restriction (DR) is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of DR, intermittent fasting (IF) and caloric restriction (CR), have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan, even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that a nutrient-related signalling molecule, the low molecular weight GTPase Cel-Rheb, has a dual role in lifespan regulation; Cel-Rheb is required for the IF-induced longevity, whereas inhibition of Cel-Rheb mimics the CR effects. We also show that Cel-Rheb exerts its effects in part via the insulin/IGF-like signalling effector DAF-16 in IF, and that Cel-Rheb is required for fasting-induced nuclear translocation of DAF-16. We find that HSP-12.6, a DAF-16 target, functions to mediate the IF-induced longevity. Furthermore, our analyses demonstrate that most of fasting-induced upregulated genes require Cel-Rheb function for their induction, and that Cel-Rheb/Cel-TOR signalling is required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling via Cel-Rheb in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway.
2008-12-15 | GSE9682 | GEO
Project description:Caloric restriction (CR) is a well-established dietary strategy known to enhance insulin sensitivity and mitigate the risk of metabolic disorders. Despite its proven benefits, the precise molecular mechanisms underlying CR's positive impacts remain incompletely elucidated. Therefore, the principal goal of this study was to identify specific proteins and pathways involved in the enhancements of insulin sensitivity attributed to sustained caloric restriction.
2025-05-06 | PXD047731 | Pride
Project description:Dietary restriction is a nutritional intervention that consistently increases life span in animals. To identify alternative, more acceptable nutritional regimes that nevertheless extend life span, we used the fruit fly Drosophila melanogaster as a model. We tested if weekly recurring nutritional regimes composed of phases of ad libitum feeding and dietary restriction can increase life span. Short periods of dietary restriction (up to 2 days) followed by longer ad libitum phases increased life span only marginally, whereas regimes comprising longer contiguous periods (3 days and more) became clearly positive, reaching similar life span extensions as those seen if dietary restriction was applied persistently. Female flies were substantially more responsive to these interventions than males. The finding that a minimal period of 3-4 days of dietary restriction is required to induce robust life span extensions was mirrored by the observation that substantial physiological and transcriptional changes occurred in a similar temporal pattern. Moreover, these dietary restriction induced changes were also detectable after switching to ad libitum feeding. Among the physiological changes induced by these phases of dietary restriction, a reduced metabolic rate and a substantial and long-lasting reduction in insulin signaling were most compelling. Age associated molecular signatures comprising mechanisms that reduce insulin signaling showed up after longer periods of dietary restriction in the fly’s fat body, thus showing how molecular alterations transduce into life span related physiological changes.
2017-12-21 | GSE95349 | GEO
Project description:Dietary restriction (DR) is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of DR, intermittent fasting (IF) and caloric restriction (CR), have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan, even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that a nutrient-related signalling molecule, the low molecular weight GTPase Cel-Rheb, has a dual role in lifespan regulation; Cel-Rheb is required for the IF-induced longevity, whereas inhibition of Cel-Rheb mimics the CR effects. We also show that Cel-Rheb exerts its effects in part via the insulin/IGF-like signalling effector DAF-16 in IF, and that Cel-Rheb is required for fasting-induced nuclear translocation of DAF-16. We find that HSP-12.6, a DAF-16 target, functions to mediate the IF-induced longevity. Furthermore, our analyses demonstrate that most of fasting-induced upregulated genes require Cel-Rheb function for their induction, and that Cel-Rheb/Cel-TOR signalling is required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling via Cel-Rheb in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway. Experiment Overall Design: We examined fasting-induced changes of the gene expression profiles in Caenorhabditis elegans. We performed the genome-wide analysis by using Affymetrix GeneChip oligonucleotide microarrays, and examined the effect of downregulation of Cel-Rheb and Cel-TOR by RNAi on the expression profiles. Five independent experiments were performed with wild type N2. Synchronized worms under six conditions (control-fed, control-fasting, Rheb RNAi-fed, Rheb RNAi-fasting, TOR RNAi-fed, and TOR RNAi-fasting) were collected and frozen with liquid nitrogen at day 4 of adulthood. Total RNA was extracted with Sepasol(R)-RNA â Super (Nacalai tesque), and purified with RNeasy Mini Kit (Qiagen), according to manufactureâs instructions. Synthesis of cDNA, in vitro transcription and biotin labelling cRNA, and hybridization to the C. elegans Genome Array (Affymetrix) were performed according to Affymetrix protocols. Hybridized arrays were scanned using an Affymetrix GeneChip Scanner. Scanned chip images were analyzed with GeneSpring GX 7.3.1 (Agilent Technologies).
2009-01-13 | E-GEOD-9682 | biostudies-arrayexpress
Project description:Reduction in expression of the INDY gene in Drosophila melanogaster and Caenorhabditis elegans prolongs life span, and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which INDY does this is unknown. In order to examine the effect that INDY might have on energy metabolism and insulin sensitivity in mammals we created the first knock out mouse model of the mammalian INDY homologue SLC13A5. Here, we show that deletion of the mammalian homologue of INDY, SLC13A5 (mINDY) in mice (mINDY-/- mice) have increased mitochondrial biogenesis, hepatic lipid oxidation, and energy expenditure, but decreased hepatic de novo lipogenesis. Loss of mIndy activates hepatic AMPK, which induces PGC-1?, inhibits ACC-2, and reduces SREBP-1c levels. In contrast to wild- type mice, mINDY-/- mice have reduced body weight and are protected from insulin resistance that evolves with high-fat feeding and aging. These studies demonstrate that mIndy functions as a novel regulator of mammalian energy metabolism and suggest that mIndy might be a novel therapeutic target for the treatment of obesity and type 2 diabetes.
2011-08-04 | GSE29984 | GEO
Project description:Gene Expression Following Transaortic Constriction in Cardiomyocyte Specific Insulin Receptor Substrate Knockout Mice
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