Long-term intranasal insulin aspart: a profile of gene expression, memory, and insulin receptors in aged F344 rats
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PROVIDER: PRJNA533832 | ENA |
REPOSITORIES: ENA
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Project description:Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin’s efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets. Outcome variables included measures of spatial learning and memory, autoradiography and immunohistochemistry of the insulin receptor, and hippocampal microarray analyses. Aged Fischer 344 rats receiving long-term (3 months) intranasal insulin did not show significant memory enhancement on the Morris water maze task. Autoradiography results showed that long-term treatment reduced insulin binding in the thalamus but not the hippocampus. Results from hippocampal immunofluorescence revealed age-related decreases in insulin immunoreactivity that were partially offset by intranasal administration. Microarray analyses highlighted numerous insulin-sensitive genes, suggesting insulin aspart was able to enter the brain and alter hippocampal RNA expression patterns including those associated with tumor suppression. Our work provides insights into potential mechanisms of intranasal insulin and insulin resistance, and highlights the importance of treatment duration and the brain regions targeted.
2019-04-20 | GSE130098 | GEO
Project description:Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin's efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets. Outcome variables included measures of spatial learning and memory, autoradiography and immunohistochemistry of the insulin receptor, and hippocampal microarray analyses. Aged Fischer 344 rats receiving long-term (3 months) intranasal insulin did not show significant memory enhancement on the Morris water maze task. Autoradiography results showed that long-term treatment reduced insulin binding in the thalamus but not the hippocampus. Results from hippocampal immunofluorescence revealed age-related decreases in insulin immunoreactivity that were partially offset by intranasal administration. Microarray analyses highlighted numerous insulin-sensitive genes, suggesting insulin aspart was able to enter the brain and alter hippocampal RNA expression patterns including those associated with tumor suppression. Our work provides insights into potential mechanisms of intranasal insulin and insulin resistance, and highlights the importance of treatment duration and the brain regions targeted.
| S-EPMC7243593 | biostudies-literature
Project description:Previous studies showed that aging in coronary arteries is associated with pro-inflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by inducing endothelial apoptosis. To test this hypothesis we characterized pro-apoptotic alterations in the phenotype of coronary arteries of aged (26 month old) and young (3 month old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was a ~4 fold increase in the number of apoptotic endothelial cells. Analysis of the expression of apoptosis-related genes (microarray, real-time PCR) showed that in aged coronary arteries there was an increased expression of TNFa, TNFb, caspase 9 and an increased presence of cleaved caspase 3 and caspase 9 (Western blotting), whereas expression of TNFR1 and that of TRADD, Bcl-2, Bcl-X(L), Bid, Bax, caspase 8 and caspase 3 were unchanged. We propose that aging-induced up-regulation of TNFa and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to the development of endothelial dysfunction and ischemic heart disease in the elderly. Keywords: repeat sample
2003-10-28 | GSE615 | GEO
Project description:Background: Perinatal iron deficiency (ID) targets the hippocampus and leads to long-term cognitive deficits. These deficits remain even after iron repletion, suggesting that further insight into the mechanisms of cognitive deficits and adjunct treatments are needed. Intranasal insulin improves cognitive deficits in adult humans with Alzheimer’s disease and type 2 diabetes and could provide benefits in ID-induced neurological dysfunction. Objective: Assess the effects of intranasal insulin administration on the hippocampal transcriptome in rat model of perinatal ID. Methods: Perinatal ID was induced using a low iron diet from gestational day 3 until postnatal day (P) 7, followed by an iron sufficient (IS) diet through P21. Intranasal insulin was administered at a dose of 0.3 IU, twice daily from P8 to P21. Hippocampi were removed on P21 from IS control, ID control, IS insulin, and ID insulin groups. Total RNA was isolated and profiled using TruSeq next-generation sequencing (Illumina). Gene expression profiles were characterized using custom Galaxy workflows and expression patterns were examined using Ingenuity Pathways Analysis (Qiagen) (n = 7-9 per group). Results: Transcriptomic profiling revealed that mitochondrial biogenesis and flux, oxidative phosphorylation, quantity of neurons, CREB signaling in neurons, and RICTOR-based mTOR signaling were disrupted with ID and positively affected by insulin treatment with the most benefit observed in the ID insulin group. Conclusions: Both perinatal ID and insulin administration altered gene expression in the developing hippocampus. Intranasal insulin treatment reversed the adverse effects of ID on many molecular pathways and should be further explored as an adjunct therapy in perinatal ID.
2023-04-20 | GSE220770 | GEO
Project description:Previous studies showed that aging in coronary arteries is associated with pro-inflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by inducing endothelial apoptosis. To test this hypothesis we characterized pro-apoptotic alterations in the phenotype of coronary arteries of aged (26 month old) and young (3 month old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was a ~4 fold increase in the number of apoptotic endothelial cells. Analysis of the expression of apoptosis-related genes (real-time PCR) showed that in aged coronary arteries there was an increased expression of TNFa, TNFb, caspase 9 and an increased presence of cleaved caspase 3 and caspase 9 (Western blotting), whereas expression of TNFR1 and that of TRADD, Bcl-2, Bcl-X(L), Bid, Bax, caspase 8 and caspase 3 were unchanged. Vascular expression and activity of TNFa convertase enzyme were preserved in aging. We propose that aging-induced up-regulation of TNFa and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to the development of endothelial dysfunction and ischemic heart disease in the elderly.
2010-06-05 | E-GEOD-619 | biostudies-arrayexpress
Project description:Previous studies showed that aging in coronary arteries is associated with pro-inflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by inducing endothelial apoptosis. To test this hypothesis we characterized pro-apoptotic alterations in the phenotype of coronary arteries of aged (26 month old) and young (3 month old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was a ~4 fold increase in the number of apoptotic endothelial cells. Analysis of the expression of apoptosis-related genes (real-time PCR) showed that in aged coronary arteries there was an increased expression of TNFa, TNFb, caspase 9 and an increased presence of cleaved caspase 3 and caspase 9 (Western blotting), whereas expression of TNFR1 and that of TRADD, Bcl-2, Bcl-X(L), Bid, Bax, caspase 8 and caspase 3 were unchanged. Vascular expression and activity of TNFa convertase enzyme were preserved in aging. We propose that aging-induced up-regulation of TNFa and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to the development of endothelial dysfunction and ischemic heart disease in the elderly. Keywords: other
2003-10-28 | GSE619 | GEO
Project description:We reveal a critical role of tanycyte insulin receptors in gating feeding state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance
2021-12-13 | GSE185074 | GEO
Project description:Insulin receptors in tanycytes gate hypothalamic insulin uptake and regulate AgRP neuronal activity
| PRJNA767609 | ENA
Project description:Despite a high degree of homology, insulin and IGF-1 receptors (IR/IGF1R) mediate distinct cellular and physiological functions. Here, using chimeric and site-mutated receptors, we demonstrate how domain differences between IR and IGF1R contribute the distinct functions of these receptors. Receptors with the intracellular domain of IGF1R show increased activation of Shc and Gab-1 and more potent regulation of genes involved in proliferation, corresponding to its higher mitogenic activity. Conversely, receptors with the intracellular domain of IR display higher IRS-1 phosphorylation, stronger regulation of genes in metabolic pathways and more dramatic glycolytic responses to hormonal stimulation. We generated mouse brown preadipocytes in which both insulin and IGF-1 receptors (IR and IGF1R) had been genetically inactivated using Cre-lox recombination. These IR and IGF1R DKO cells were then reconstituted with wild-type mouse IR, IGF1R, or one of two chimeric receptors: IR/IGF1R with the IR extracellular domain (ECD) fused to the IGF1R transmembrane and intracellular domains (ICD) and IGF1R/IR with the ECD of IGF1R fused to the ICD domains of IR. Three independent clones for each line were used for the study. For expression analysis, we serum-starved the preadipocytes clones overnight and stimulated cells with 100 nM insulin, IGF-1 or vehicle for 6 h, and subjected the cellular RNA to analysis using Affymetrix Mouse Gene 2.0 ST arrays.
2016-07-01 | E-GEOD-81921 | biostudies-arrayexpress
Project description:Although aging is a physiological process to which all organisms are subject, the presence of obesity and type 2 diabetes accelerates biological aging. Recent studies have demonstrated the causal relationships between dietary interventions suppressing obesity and type 2 diabetes and delaying the onset of age-related endocrine changes. Curcumin, a natural antioxidant, has putative therapeutic properties such as reinstating insulin sensitivity in obese mice. However, how curcumin contributes to maintaining insulin homeostasis in aged organisms largely remains unclear. Thus, the objective of this study is to examine the pleiotropic effect of dietary curcumin on insulin homeostasis in a diet-induced obese (DIO) aged mouse model. Aged (18-20 months old) male mice given a high-fat high-sugar diet supplemented with curcumin displayed a different metabolic phenotype compared to mice given a high-fat high-sugar diet alone. Furthermore, curcumin supplementation altered hepatic gene expression profiling, especially insulin signaling and senescence pathways. We then mechanistically investigated how curcumin functions to fine-tune insulin sensitivity. We found that curcumin supplementation increased hepatic insulin degrading enzyme (IDE) expression levels and preserved islet integrity, both of which are beneficial during aging. Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age-induced metabolic diseases.
2021-11-04 | GSE186971 | GEO