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Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice.

ABSTRACT: 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 (WT^AL and KO^AL) or fed a 30% DR diet (WT^DR or KO^DR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WT^DR and KO^AL 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 KO^AL and KO^DR, 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.

SUBMITTER: Page MM

PROVIDER: S-EPMC5990393 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 in mice

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

Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 in mice

Project description:Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 in mice

| PRJNA418412 | ENA

The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.

Project description:Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization.

| S-EPMC3338610 | biostudies-literature

A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration.

Project description:Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.

| S-EPMC1316270 | biostudies-other

Influence of dietary restriction and low-intensity exercise on weight loss and insulin sensitivity in obese equids.

Project description:BackgroundThe importance of including exercise with dietary modification for the management of obese equids is not clearly understood.ObjectivesTo evaluate the effect of a practical low-intensity exercise regimen, in addition to dietary restriction, on indices of insulin sensitivity (SI) and plasma adipokine concentrations in obese equids.AnimalsTwenty-four obese (body condition score [BCS]???7/9) horses and ponies.MethodsOver a 12-week period, animals received either dietary restriction only (DIET) or dietary restriction plus low-intensity exercise (DIET+EX). All animals were provided with a restricted ration of grass hay at 1.25% body weight (BW) on a dry matter basis, providing 82.5% estimated digestible energy requirements. The DIET+EX group undertook low-intensity exercise 5 days per week on an automated horse walker. Before and after weight loss, total body fat mass (TBFM) was determined, indices of SI were calculated using minimal model analysis of a frequently sampled IV glucose tolerance test, and adipokines plus inflammatory biomarkers were measured using validated assays.ResultsDecreases in BCS, BW, and TBFM were similar between groups (all P?>?.05). After weight loss, animals in both groups had decreased basal insulin and leptin concentrations, and increased adiponectin concentrations (all P?<?.001). Furthermore, animals in the DIET+EX group had significantly improved SI and decreased serum amyloid A concentrations relative to animals in the DIET group (both P?=?.01).Conclusions and clinical importanceRegular low-intensity exercise provided additional health benefits compared with dietary restriction alone in this population of obese equids.

| S-EPMC6335535 | biostudies-literature

Transcriptional response to dietary restriction in Drosophila melanogaster.

Project description:Dietary restriction (DR) extends lifespan in a wide variety of organisms. Although several genes and pathways associated with this longevity response have been identified, the specific mechanism through which DR extends lifespan is not fully understood. We have recently developed a novel methodology to screen for transcriptional changes in response to acutely imposed DR upon adult Drosophila melanogaster and identified groups of genes that switch their transcriptional patterns from a normal diet pattern to a restricted diet pattern, or 'switching genes'. In this current report we extend our transcriptional data analysis with gene set enrichment analysis to generate a pathway-centered perspective. The pattern of temporal behavior in response to the diet switch is strikingly similar within and across pathways associated with mRNA processing and protein translation. Furthermore, most genes within these pathways display an initial spike in activity within 6-8h from the diet switch, followed by a coordinated, partial down-regulation after 24h. We propose this represents a stereotypical response to DR, which ultimately leads to a mild but widespread inhibition of transcriptional and translational activity. Inhibition of the protein synthesis pathway has been observed in DR in other studies and has been shown to extend lifespan in several model organisms.

| S-EPMC4177363 | biostudies-literature

Dietary sodium restriction decreases insulin secretion without affecting insulin sensitivity in humans.

Project description:ContextInterruption of the renin-angiotensin-aldosterone system prevents incident diabetes in high-risk individuals, although the mechanism remains unclear.ObjectiveTo test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system or exogenous aldosterone impairs insulin secretion in humans.DesignWe conducted a randomized, blinded crossover study of aldosterone vs vehicle and compared the effects of a low-sodium versus a high-sodium diet.SettingAcademic clinical research center.ParticipantsHealthy, nondiabetic, normotensive volunteers.InterventionsInfusion of exogenous aldosterone (0.7 μg/kg/h for 12.5 h) or vehicle during low or high sodium intake. Low sodium (20 mmol/d; n = 12) vs high sodium (160 mmol/d; n = 17) intake for 5-7 days.Main outcome measuresChange in acute insulin secretory response assessed during hyperglycemic clamps while in sodium balance during a low-sodium vs high-sodium diet during aldosterone vs vehicle.ResultsA low-sodium diet increased endogenous aldosterone and plasma renin activity, and acute glucose-stimulated insulin (-16.0 ± 5.6%; P = .007) and C-peptide responses (-21.8 ± 8.4%; P = .014) were decreased, whereas the insulin sensitivity index was unchanged (-1.0 ± 10.7%; P = .98). Aldosterone infusion did not affect the acute insulin response (+1.8 ± 4.8%; P = .72) or insulin sensitivity index (+2.0 ± 8.8%; P = .78). Systolic blood pressure and serum potassium were similar during low and high sodium intake and during aldosterone infusion.ConclusionsLow dietary sodium intake reduces insulin secretion in humans, independent of insulin sensitivity.

| S-EPMC4184066 | biostudies-literature

Insulin receptor substrate 1 (IRS1) variants confer risk of diabetes in the Boston Puerto Rican Health Study.

Project description:ObjectivePublished data concerning associations between IRS1 variants and type 2 diabetes and related traits have been inconsistent. We examined the relationship between common variants in IRS1, type 2 diabetes, and related traits including insulin resistance, hyperglycemia and DNA damage in the Boston Puerto Rican Health Study.MethodsWe genotyped six common IRS1 variants in an adult Puerto Rican population (n=1132) and tested for association with risk of type 2 diabetes and related traits.ResultsSNPs rs934167 and rs1801123 showed significant association with fasting glucose concentrations (p = 0.005 and p = 0.016, respectively) and rs934167 showed significant association with plasma insulin levels (p = 0.005). Carriers of the rs934167 minor allele had significantly higher HOMA-IR and lower QUICKI (p = 0.001 and p = 0.001, respectively), and a 40% and 58% greater likelihood of being hyperglycaemic or hyperinsulinemic (OR = 1.40 and 1.58; p = 0.013 and 0.002, respectively). However, they exhibited only a marginally significant trend towards having type 2 diabetes (OR=1.27, p = 0.077). Furthermore, carriers of the haplotype C-T of the rs934167 and rs1801123 minor alleles showed consistent patterns of associations after correction for multiple testing. In addition, the G972R (rs1801278) minor allele was significantly associated with higher urinary 8-OHdG concentrations (p = 0.020) and plasma CRP levels (p = 0.035).ConclusionsOur results support IRS1 variants associated with type 2 diabetes risk in adult Puerto Ricans. Moreover, we report the novel finding that IRS1 variant G972R (rs1801278) may contribute to oxidative DNA damage and inflammation.

| S-EPMC4428925 | biostudies-literature

Genes regulated by caloric restriction have unique roles within transcriptional networks.

Project description:Caloric restriction (CR) has received much interest as an intervention that delays age-related disease and increases lifespan. Whole-genome microarrays have been used to identify specific genes underlying these effects, and in mice, this has led to the identification of genes with expression responses to CR that are shared across multiple tissue types. Such CR-regulated genes represent strong candidates for future investigation, but have been understood only as a list, without regard to their broader role within transcriptional networks. In this study, co-expression and network properties of CR-regulated genes were investigated using data generated by more than 600 Affymetrix microarrays. This analysis identified groups of co-expressed genes and regulatory factors associated with the mammalian CR response, and uncovered surprising network properties of CR-regulated genes. Genes downregulated by CR were highly connected and located in dense network regions. In contrast, CR-upregulated genes were weakly connected and positioned in sparse network regions. Some network properties were mirrored by CR-regulated genes from invertebrate models, suggesting an evolutionary basis for the observed patterns. These findings contribute to a systems-level picture of how CR influences transcription within mammalian cells, and point towards a comprehensive understanding of CR in terms of its influence on biological networks.

| S-EPMC2688445 | biostudies-other

High-fat dietary restriction in mice induces substrate efficiency and improves metabolic health

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

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