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Glucose Shortens the Lifespan of Caenorhabditis elegans by Down-Regulating Aquaporin Gene Expression

ABSTRACT: Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on lifespan itself. We found that adding a small amount of glucose to the medium (0.1-2%) shortened the lifespan of C. elegans. Glucose shortened lifespan by inhibiting the activities of lifespan-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the down-regulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the lifespan-shortening effect of glucose, and that aqp-1 may act cell non-autonomously as a feedback regulator in the insulin/IGF-1 signaling pathway. Insulin down-regulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together these findings raise the possibility that a low-sugar diet might have beneficial effects on lifespan in higher organisms. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE18563 | GEO | 2010/01/01

SECONDARY ACCESSION(S): PRJNA121381

REPOSITORIES: GEO

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Glucose Shortens the Lifespan of Caenorhabditis elegans by Down-Regulating Aquaporin Gene Expression

Project description:Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on lifespan itself. We found that adding a small amount of glucose to the medium (0.1-2%) shortened the lifespan of C. elegans. Glucose shortened lifespan by inhibiting the activities of lifespan-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the down-regulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the lifespan-shortening effect of glucose, and that aqp-1 may act cell non-autonomously as a feedback regulator in the insulin/IGF-1 signaling pathway. Insulin down-regulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together these findings raise the possibility that a low-sugar diet might have beneficial effects on lifespan in higher organisms. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE18561: Adult C. elegans: Control daf-2 mutants treated with daf-16 RNAi vs. daf-2 mutants treated with empty vector RNAi GSE18562: Adult C. elegans: Control OP50 culture vs. OP50 + 2% glucose culture

2010-05-16 | E-GEOD-18563 | biostudies-arrayexpress

Microarray expression analysis of Aquaporin-9 (AQP9) knockout effect in fasted C57Bl/6 mice

Project description:Aquaporin-9 is a glycerol, urea and hydrogen peroxide channel, with highest expression in the liver. We have previously demonstrated that AQP9 is required for hepatocyte glycerol uptake and thus for gluconeogenesis from glycerol. AQP9 gene deletion in db/db mice of the C57BLKS background results in improved glycemia, while glycemia in normal mice is unaffected even during starvation, when glycerol is an important gluconeogenic substrate. To identify mechanisms that compensate the lack of glycerol uptake for gluconeogenesis, we performed a gene expression profiling and metabolomics study.

2021-12-06 | E-MTAB-5849 | biostudies-arrayexpress

Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice

Project description:Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor deficient (db/db) obese mice on a C57BL/6×C57BLKS mixed genetic background. Furthermore, shRNA mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in a diet induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57BL/6 background. Aqp9wt db/db and Aqp9-/- db/db mice did not differ in body weight and liver TAG contents. On the C57BL/6 genetic background we observed elevated plasma glucose in Aqp9-/- db/db mice (+ 1.1 mM, life-time average) while plasma insulin concentration was reduced at time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9wt db/db and Aqp9-/- db/db mice. Liver transcriptional profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%), glucose (+24%) and reduction in threonate (all at q<0.1) in Aqp9-/- db/db mice compared to controls. Metabolite profiling thus confirms a role of AQP9 in glycerol metabolism of obese C57BL/6 db/db mice. In this animal model of obesity Aqp9 gene deletion elevates plasma glucose and does not alleviate hepatosteatosis.

2015-09-28 | MTBLS219 | MetaboLights

Obese Insulin Resistant Humans with Compensatory Hyperinsulinemia Dissociate Lipolysis from Glycemia as Possible Adaptive Response to Fatness

Project description:High blood levels of free fatty acids link obesity with type-2 diabetes, but this connection remains poorly understood. We have investigated lipolysis and glucose homeostasis in recently diagnosed obese type-2 diabetics; in obese insulin resistant non-diabetic subjects (obese-IR) matched for age, sex, body composition and fasting insulin levels; and in healthy lean individuals. Our results show that obese-IR dissociate lipolysis from glycemic control, revealing that the action of compensatory hyperinsulinemia on blood glucose is not mediated by reduced lipolysis. In the obese adipose tissue free fatty acids and glycerol levels were elevated in spite of high local levels of insulin or lactate; correlated with adipocyte size and metabolic inflammation, with reduced adipose tissue mRNA levels of genes implicated in beta-adrenergic signaling, de-novo lipogenesis, and increased expression of genes implicated in adipose tissue hyperplasia. These results shed light on the nature of the interaction between lipolysis and glucose homeostasis and indicate an possible adaptive response to fatness.

2021-04-07 | GSE141432 | GEO

SMOC1 as a therapeutic target for type 2 diabetes

Project description:Inter-tissue communication is a fundamental feature of systemic metabolic regulation and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and potent regulator of glucose homeostasis. Acute administration of recombinant SMOC1 improves glycemic control and insulin sensitivity, independent of changes in insulin secretion. SMOC1 exerts its favourable glycemic effects by inhibiting cAMP-PKA-CREB signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Over expression of SMOC1 in the liver or once-weekly injections of a stabilized SMOC1-FC fusion protein induces durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without significant adverse effects on adiposity, liver histopathology or inflammation. Furthermore, SMOC1 correlates with systemic insulin sensitivity and is decreased in obese, insulin resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.

2020-08-21 | PXD015767 | Pride

Neural crest cells bulldoze through the microenvironment using water channel proteins to stabilize filopodia

Project description:Neural crest migration requires cells to move through dense extracellular matrix and mesoderm to reach targets throughout the vertebrate embryo. Here, we use high-resolution microscopy, computational modeling, and in vitro and in vivo cell invasion assays to investigate the function of Aquaporin-1 (AQP-1) signaling. We find that migrating cranial neural crest cells express AQP-1 mRNA and protein within cell filopodia, implicating a biological role for water channel protein function during invasion. Differential AQP-1 levels affect neural crest cell speed, direction, and the length and stability of cell filopodia. Further, AQP-1 enhances matrix metalloprotease (MMP) activity and phosphorylated focal adhesion kinases (pFAK). Co-localization of AQP-1 expression with EphB guidance receptors in the same migrating neural crest cells raises novel implications for the concept of guided bulldozing by lead cells during migration.

2019-12-16 | GSE121131 | GEO

Aquaporin-11 knockout effect on kidney

Project description:Aquaporin-11 (AQP11), a new member of the aquaporin family, is localized in the endoplasmic reticulum (ER). Aqp11–/– mice neonatally suffer from polycystic kidneys derived from the proximal tubule. Its onset is proceeded by the vacuolization of ER. However, the mechanism for the formation of vacuoles and the development of cysts remain to be clarified. Here, we show that Aqp11–/– mice and polycystic kidney disease animals share a common pathogenic mechanism of cyst formation. Keywords: Geneexpression profile of Aqp11 knokout mouse kidney

2008-10-01 | GSE10634 | GEO

Benefits of a 6 week supplementation of sebacic acid on a mouse model of type 2 diabetes (db/db mice)

Project description:This study aimed at investigating the impact of chronic ingestion of sebacic acid (SA), a 10 carbons medium-chain dicarboxylic acid, on glycemic control in a mouse model of type 2 diabetes (db/db mice). Three groups of 15 mice were fed for 6 weeks either a chow diet (Ctrl), or a chow diet supplemented with 1.5% or 15% (SA1.5% and SA15% resp.) energy from SA. Fasting glycemia was measured once a week and HbA1c before and after supplementation. An oral glucose tolerance test (OGTT) was performed at the end of the supplementation. Gene expression was determined by transcriptomic analysis on the liver of the Ctrl and SA15% groups. Results-After 42 days of supplementation, fasting glycemia and HbA1c were ~70% and ~25% lower in the SA15% group compared to other groups showing a beneficial effect of SA on hyperglycemia. During OGTT, blood glucose area under the curve (AUC) was reduced after SA15% compared to other groups. This effect was associated with a tendency for an improved insulin response. In the liver, Pck1 and FBP mRNA were statistically decreased in the SA15% compared to Ctrl suggesting a reduced hepatic glucose output induced by SA. Conclusions-Dietary supplementation of SA largely improves glycemic control in a mouse model of type 2 diabetes. This beneficial effect may be due (1) to a reduced hepatic glucose output resulting from transcriptional down regulation of key gluconeogenesis genes and (2) to an improved glucose induced-insulin secretion. Microarray analysis of 6-8 wk old male BKS.Cg-m+/+Leprdb/J 000642 db/db mice. 2 groups. n=15/group: 1) Control group. 2) Sebacic acid high dose group - 15% (77.6g/kg food, â??9g/kg body weight per day).

2010-10-29 | E-GEOD-21083 | biostudies-arrayexpress

Benefits of a 6 week supplementation of sebacic acid on a mouse model of type 2 diabetes (db/db mice)

2010-10-29 | GSE21083 | GEO

Signaling Pathways in Vasopressin-Mediated Regulation of Aquaporin-2

Project description:Vasopressin controls water excretion by regulating the water channel protein, aquaporin 2. Vasopressin acts in the renal collecting duct by binding to a G-protein coupled receptor and activating protein kinase A (PKA). Signaling events beyond PKA are largely unknown. Ultra-deep phosphoproteomic analysis of collecting duct cells isolated from rat kidneys identified and quantified 10,738 phosphorylation sites. Vasopressin significantly altered the abundance of only 219 of these phosphorylation sites, suggesting a highly selective effect on cell signaling. The regulated sites were mapped to cellular processes shown in prior studies to be involved in aquaporin-2 regulation. The mapping and full data set was used to create an online data resource to guide future studies.

2020-05-25 | PXD011245 | Pride

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