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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Beta cell overexpression of HSD11B1 in high fat fed mice

ABSTRACT: To model the potential diabetogenic effects of higher level of HSD11B1 in b-cells of the pancreas in vivo, we created a transgenic model overexpressing HSD11B1 under the mouse insulin I promoter (MIP-HSD1) in diabetes-prone C57Bl/KsJ mice. KsJ wild type and MIP-HSD1 heterozygous mice have been high fat fed for 12 weeks. Pancreata have been perfused with collagenase and islets isolated by hand picking. Isolated islets (around 500) coming from at least 3 mice (around 200/mice) have been directly lysed in Trizol. Total RNA have been extracted by Trizol plus RNA Purification Kit (invitrogen). Four biological replicates per group: Wild type KsJ mice on High Fat diet (KsJ1, KsJ2, KsJ3, KsJ4) and MIP-HSD1 transgenic mice on High Fat diet (MIP1, MIP2, MIP3, MIP4) were used to prepare RNA for microarray analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Donald Dunbar

PROVIDER: E-GEOD-23161 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Beta cell overexpression of HSD11B1 in high fat fed mice

Project description:To model the potential diabetogenic effects of higher level of HSD11B1 in b-cells of the pancreas in vivo, we created a transgenic model overexpressing HSD11B1 under the mouse insulin I promoter (MIP-HSD1) in diabetes-prone C57Bl/KsJ mice. KsJ wild type and MIP-HSD1 heterozygous mice have been high fat fed for 12 weeks. Pancreata have been perfused with collagenase and islets isolated by hand picking. Isolated islets (around 500) coming from at least 3 mice (around 200/mice) have been directly lysed in Trizol. Total RNA have been extracted by Trizol plus RNA Purification Kit (invitrogen).

2011-06-30 | GSE23161 | GEO

Palmitoylation couples insulin hypersecretion with β-cell failure in diabetes

Project description:Hyperinsulinemia often precedes type 2 diabetes but its role in disease progression is unknown. Palmitoylation, a protein modification implicated in regulated exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). We found altered APT1 biology in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic human islets caused insulin hypersecretion. Chow fed global and islet specific APT1 knockout mice had enhanced glucose tolerance due to islet autonomous increased glucose-stimulated insulin secretion. APT1 deficiency did not affect islet calcium dynamics but prolonged insulin granule fusion. Using palmitoylation proteomics, we identified Scamp1 as an APT1 substrate that localized to insulin secretory granules. Knockdown of Scamp1 caused insulin hypersecretion. APT1 deficient insulinoma cells subjected to nutrient excess had increased apoptosis, and expression of a mutated Scamp1 incapable of being palmitoylated in APT1 deficient cells rescued insulin hypersecretion and nutrient induced apoptosis. Compared to APT1 sufficient controls, high fat fed islet specific APT1 knockout mice and global APT1 deficient db/db mice showed increased -cell failure. These findings suggest that the depalmitoylation enzyme APT1 is regulated in human islets, and that APT1 deficiency causes insulin hypersecretion leading to -cell failure, modeling the evolution of some forms of human type 2 diabetes.

2023-11-05 | PXD038554 | Pride

RNA-Seq analysis of mouse Zfp92 knockout vs wild-type adult pancreatic islets

Project description:Zfp92, a repressive KRAB domain-containing zinc-finger protein, was identified by Gene Co-expression Network analysis to be an interesting candidate gene involved in endocrine specification and maturation. We examined the role of Zfp92, a KRAB-ZFP that is highly expressed in pancreatic islets of adult mice, by analyzing global Zfp92 knockout (KO) mice. Adult Zfp92 KO animals exhibited only mild changes in glucose homeostasis and no change in islet structure, although, male KO mice exhibited decreased growth, and female KO mice exhibited increased body fat accumulation on a high fat diet. We found that Zfp92 regulates a subset of transposable elements as well as Mafb, a transcription factor involved in islet development.

2022-12-02 | E-MTAB-11637 | biostudies-arrayexpress

Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth

Project description:Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-HSD1 (encoded by Hsd11b1). Here we find that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth but reduced in vivo tumor progression, which corresponded with increased frequencies of tumor-infiltrating CD8+ T cells (TIL) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of Tconv activation in tumor-infiltrating Treg. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11β-HSD1 reduced tumor growth to the same degree as gene knockout, and rendered immunotherapy-resistant tumors susceptible to PD-1 blockade. Given that HSD11B1 expression is upregulated in many human tumors and that inhibition of 11β-HSD1 is well-tolerated in clinical studies, these data suggest that targeting 11β-HSD1 may be a beneficial adjunct in cancer therapy.

2023-09-20 | GSE231303 | GEO

Role of Ascl1 in pancreatic beta cell response to metabolic stress

Project description:To determine the role of Ascl1 in beta cell development, function, and metabolic stress response, we generated beta cell specific Ascl1 knockout mice and assessed their glucose homeostasis, islet morphology, and gene expression after feeding a normal diet, a high fat diet (HFD) for 12 weeks, or on a background of Abcc8 (KATP channel subunit) knockout mice. For the RNA-seq analysis, islets from male Ascl1betaKO and littermate control mice (N = 4 for each genotype and condition) were collected from three different conditions: 1) normal diet fed 2) HFD fed for 12 weeks, 3) on a background of homozygous Abcc8 allele.

2023-10-05 | E-MTAB-13355 | biostudies-arrayexpress

Transcription profiling of pancreatic islet implanted transgenic (expressing survivini) in mice

Project description:Transgenic mice were generated that expressed the inhibitor of apoptosis and mitotic regulator survivin in pancreatic islet beta cells. Control non-transgenic or transgenic islets were then used in a model of islet transplantation in diabetic recipient mice and tested for their ability to correct hyperglycemia and allow long-term engraftment of tranplanted islets in vivo. Control or transgenic islets were analyzed by chip microarray for potential transcriptional changes associated with transgenic expression of survivin, in vivo.

2006-01-16 | E-MEXP-536 | biostudies-arrayexpress

A nuclear-localized red fluorescence knock-in reporter allele for mouse pancreatic beta-cells

Project description:In this study, we generated a novel nuclear-localized red fluorescence knock-in reporter allele (Ins2.Apple) for mouse pancreatic beta-cells. Beta-cells were isolated by FACS from 60-day-old mice, segregated by sex, and RNA-sequencing was performed to assess sex-specific differences in beta-cell gene expression profiles. We also isolated beta-cells (by FACS) from MIP-GFP mice at 60 days of age. RNA-sequencing was performed, and was compared to that of Ins2.Apple beta cells, to assess gene expression changes brought on by the presence of the MIP-GFP transgene.

2018-12-15 | E-MTAB-6329 | biostudies-arrayexpress

Hippocampal gene expression in aged and young HSD1 knockout mice

Project description:Mice deficient in the glucocorticoid-regenerating enzyme 11Î²-HSD1 resist age-related spatial memory impairment. To investigate the mechanisms/pathways involved, we used microarrays to identify differentially expressed hippocampal genes that associate with cognitive ageing and 11Î²-HSD1. Aged wild-type mice were separated into memory-impaired and unimpaired relative to young controls according to their performance in the Y-maze. All individual aged 11Î²-HSD1-deficient mice showed intact spatial memory. The majority of differentially expressed hippocampal genes were increased with ageing (e.g. immune/inflammatory response genes) with no genotype differences. However, the neuronal-specific transcription factor, Npas4 and immediate early gene, Arc were reduced (relative to young) in the hippocampus of memory-impaired but not unimpaired aged wild-type or aged 11Î²-HSD1-deficient mice. Quantitative RT-PCR and in situ hybridization confirmed reduced Npas4 and Arc mRNA expression in memory-impaired aged wild-type mice. These findings suggest that 11Î²-HSD1 may contribute to the decline in Npas4 and Arc mRNA levels associated with memory impairment during ageing, and that decreased activity of synaptic plasticity pathways involving Npas4 and Arc may, in part, underlie the memory deficits seen in cognitively-impaired aged wild-type mice. 20 samples, 5 groups of 4 biological replicates each. Young, Wild Type animals are overall controls

2015-11-23 | E-GEOD-68515 | biostudies-arrayexpress

Differential expression of genes in pancreatic islet of C57Bl/6J on high fat diet

Project description:Male C57Bl/6J mice were fed 45%kcal fat diet (HF) or regular rodent chow (NC) from 4 weeks to 16 weeks of age. Gene expression was compared between RNA obtained from pancreatic islets of HF fed mice and NC mice. RNA samples from 4 NC group and 4 HF groups were analyzed using GeneChip Mouse Expression Arrays MOE 430v2 (Affymetrix).

2011-11-20 | E-GEOD-23325 | biostudies-arrayexpress

Reduced insulin secretion in WFS1-deficient mice may be related to downregulation of Trpm5

Project description:Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. WFS1 encodes an endoplasmic reticulum resident transmembrane protein. The Wfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of the present study was to describe the insulin secretion and transcriptome of pancreatic islets in WFS1-deficient mice. WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KO pancreatic islets secreted less insulin after stimulation with 2 and 10 mM glucose and with tolbutamide solution compared to WT and Wfs1HZ islets, but not after stimulation with 20 mM glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. After stimulation with 2 mM glucose solution the proinsulin/insulin ratio in Wfs1KO was significantly higher than that of WT and Wfs1HZ. RNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated in WFS1-deficient mice. Functional annotation of RNA sequencing results showed that WFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. These findings suggest an interactive role of WFS1 and TRPM5 in insulin secretion. 12 samples: three genotypes, 4 individuals in each genotype

2015-02-14 | E-GEOD-65929 | biostudies-arrayexpress

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