Transcription profiling of mouse anorexia-cachexia syndrome in anx/anx mouse model
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Lauro Sumoy
PROVIDER: E-GEOD-11426 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The anorexia mouse model, anx/anx, carries a spontaneous mutation not yet identified and homozygous mutants are characterized by anorexia-cachexia, growth failure and abnormal behavior, such as head weaving, hyperactivity, and ataxia. In order to test if miRNA machinery could influence the phenotype of these mice, RNA samples from mutant and wild type hypothalamus and cortex were hybridized to microarray chips based on LNA probes allowing the detection of 279 mouse miRNAs and to Agilent 44k chips to analyze the whole mRNA transcriptome. In anx/anx hypothalamus we found that predicted miRNA targets were preferentially upregulated in a lineally dependent manner according to the number of miRNA target sites in each mRNA (p = 10-139). Conversely, we observed that in anx/anx cortex mRNAs predicted to be targeted by miRNAs were preferentially downregulated (p < 10-74), suggesting a de-regulation of genes targeted by miRNAs in two brain areas in anx/anx mice. A closer look to the mRNA transcriptome allowed us to identify upregulation of five miRISC genes, including Dgcr8 and Fmr1, and Ago2, which were later confirmed by Real Time PCR. The results suggest that miRNA machinery might be impaired in anx/anx mice and propose its involvement in inflammatory/cancer-associated anorexia-cachexia. The data also support the previously reported link between miRNA machinery and ataxia. Further functional studies and the cloning of the anx gene should be done in order to elucidate the causality of miRNA machinery and miRNA target de-regulation, its relation with the anx/anx phenotype and to propose this mouse as a model for miRNA research. Total RNA expression profile comparison between 3 pairs of anx/anx mice and wild type littermates in brain neocortex. MicroRNA expression profile comparison between 3 pairs of anx/anx mice and wild type littermates in brain neocortex.
2012-12-08 | E-GEOD-26003 | biostudies-arrayexpress
Project description:Anorexia can occur as a serious complication of chronic disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. We studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after an intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6. C57BL/6 mice were intraperitoneally injected with TNFalpha, IL-6 Low, IL-6 High, combination TNF+IL-6 Low or combination TNF+IL-6 High. Each group comprised of 12 animals, of which 6 animals were used for transcriptomics.
2016-05-31 | E-GEOD-69151 | biostudies-arrayexpress
Project description:Anorexia is a common symptom among cancer patients and contributes to malnutrition and insufficient food intake. In cancer-induced anorexia, food intake regulation in the hypothalamus appears to be impaired. A negative energy balance persists and accelerates muscle wasting and malnutrition. Moreover, it strongly affects mortality and survival in these patients. Here, we show that the neuropeptide Y system (NPY) appears to fail to respond adequately to changes in energy balance during cancer cachexia. In addition, we investigate the connection between serotonin and NPY release in hypothalamic cell lines. Lewis Lung tumour cells were intramuscularly inoculated 6w old male C57BL/6 mice. Body weight and food intake were measured 3 times a week. On day 10, 14 and 17 hypothalamus was dissected and used for gene expression profiling.
2014-10-31 | E-GEOD-57188 | biostudies-arrayexpress
Project description:Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still able to adapt adequately to changes in energy balance. Therefore studying the changes that occur on appetite regulators in the hypothalamus might reveal targets for treatment of cancer-induced eating disorders. By applying transcriptomics, many appetite regulating systems in the hypothalamus could be taken into account, providing an overview of changes that occur in the hypothalamus during tumour growth. We show that hypothalamic expression of orexigenic neuropeptides NPY and AgRP was higher, whereas expression of anorexigenic genes CCK and POMC were lower in TB compared to controls. In addition, serotonin and dopamine signalling pathways were found to be significantly altered in TB mice. Serotonin levels in brain showed to be lower in TB mice compared to control mice, while dopamine levels did not change. Moreover, serotonin levels inversely correlated with food intake. Transcriptomic analysis of the hypothalamus of cachectic TB mice with an increased food intake showed changes in NPY, AgRP and serotonin signalling. Serotonin levels in the brain showed to correlate with changes in food intake. Targeting these systems seems a promising strategy to avoid the development of cancer-induced eating disorders. C26-colon adenocarcinoma cells were subcutaneously inoculated in CDF1 mice. After 20 days, hypothalami were dissected and subjected to gene expression profiling. The total dataset consists of 2 parts; dataset 1, a pilot stuy in which mice were injected with increasing number of tumour cells and pooled samples were arrayed; and dataset 2, the main study in which mice were injected with 1 million tumour cells and samples were individually arrayed.
2013-11-14 | E-GEOD-44080 | biostudies-arrayexpress
Project description:Systemic acute inflammatory signals can cause profound anorexia by disrupting the physiological appetite regulation in the hypothalamic milieu. Conversely, obesity related chronic inflammation of the hypothalamus can disturb anorexigenic signals and promote abnormal body weight control. The aim of the present study was to compare the global hypothalamic endophenotype in C57/Bl6 mice exposed to a high-fat diet or with acute illness mediated by LPS. Ten-week old male C57/Bl6 mice (n=18) were randomly divided into four groups; the control 1 group (n =3) was fed a normal diet whereas the high-fat diet (HFD) group (n =6) was fed a high-fat diet for eight weeks. The control 2 group (n=3) received an intraperitoneal injection of saline whereas the LPS group (n=6) received an intraperitoneal injection of LPS. Mice were sacrificed 18-hr post-injection. Both control 2 and LPS groups were fed a normal diet for eight weeks before the injection. The hypothalamic regions were removed and analysed using a 2D LC-MS methodology. The proteomic analysis profiled 9,235 proteins (q<0.05) across all biological states, of which 522 proteins were found modulated in the HFD group and another 579 in the LPS group. The proteomic profiles demonstrated that the systemic acute inflammation linked with anorexia induced a negative feedback loop of appetite control in the hypothalamus, suggesting an effort to re-establish homeostasis. By contrast, the chronic inflammation associated with obesity initiated a “perpetual cycle” of positive feedback enhancement of appetite regulation further exacerbating positive energy balance.
2018-01-29 | PXD002119 | Pride
Project description:Sarcopenia has been recognized as an emerging complication of type 2 diabetes mellitus (T2DM). Currently, the pathogenesis of T2DM-related sarcopenia remains unclear. The aim of this study was to investigate the molecular mechanisms and potential therapeutic targets for T2DM-related sarcopenia. In this study, a T2DM-related sarcopenia mouse model was established using db/db mice. Proteins extracted from the gastrocnemius muscles of db/db mice and littermate control db/m mice were analyzed by a 4D label-free quantitative proteomics approach. A total of 131 upregulated and 68 downregulated proteins were identified as differentially expressed proteins (DEPs). Bioinformatics analysis revealed that DEPs were significantly enriched in lipid metabolism. Protein–protein interaction network analysis revealed that six hub proteins, including ACOX1, CPT2, ECI2, ACADVL, ACADL, and ECH1, were involved in the fatty acid oxidation. The hub protein-transcription factor-miRNA network was also constructed through the NetworkAnalyst tool. Finally, the hub proteins were validated by western blotting and immunohistochemistry and further confirmed to be significantly negatively correlated with the muscle mass and grip strength. Our study suggested that lipid metabolism, especially excessive fatty acid oxidation, may be a crucial contributor to the progression of T2DM-related sarcopenia and a common cause of the interrelationship between T2DM and sarcopenia.
2024-10-17 | PXD051462 | Pride
Project description:Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still able to adapt adequately to changes in energy balance. Therefore studying the changes that occur on appetite regulators in the hypothalamus might reveal targets for treatment of cancer-induced eating disorders. By applying transcriptomics, many appetite regulating systems in the hypothalamus could be taken into account, providing an overview of changes that occur in the hypothalamus during tumour growth. We show that hypothalamic expression of orexigenic neuropeptides NPY and AgRP was higher, whereas expression of anorexigenic genes CCK and POMC were lower in TB compared to controls. In addition, serotonin and dopamine signalling pathways were found to be significantly altered in TB mice. Serotonin levels in brain showed to be lower in TB mice compared to control mice, while dopamine levels did not change. Moreover, serotonin levels inversely correlated with food intake. Transcriptomic analysis of the hypothalamus of cachectic TB mice with an increased food intake showed changes in NPY, AgRP and serotonin signalling. Serotonin levels in the brain showed to correlate with changes in food intake. Targeting these systems seems a promising strategy to avoid the development of cancer-induced eating disorders. C26-colon adenocarcinoma cells were subcutaneously inoculated in CDF1 mice. After 20 days, hypothalami were dissected and subjected to gene expression profiling. The total dataset consists of 2 parts; dataset 1, a pilot stuy in which mice were injected with increasing number of tumour cells and pooled samples were arrayed; and dataset 2, the main study in which mice were injected with 1 million tumour cells and samples were individually arrayed.
2013-11-14 | E-GEOD-44081 | biostudies-arrayexpress
Project description:Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. We also discovered pathological proteomic signatures consistent with defects in lysosomal function and indicative of abnormal lipid metabolism. CLN3-deficient microglia were unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation.
2024-10-23 | PXD048550 | Pride
Project description:The anx/anx mouse displays poor appetite and lean appearance and is considered a good model for the study of anorexia nervosa. To identify new genes involved in feeding behavior and body weight regulation we performed an expression profiling in the hypothalamus of the anx/anx mice. Using commercial microarrays we detected 156 differentially expressed genes and validated 92 of those using TaqMan low-density arrays. Our results showed an enrichment of deregulated genes involved in cell death, cell morphology and cancer as well as an alteration of several signaling circuits involved in energy balance including neuropeptide Y and melanocortin signaling. The expression profile along with the phenotype let us to conclude that anx/anx mice resemble the anorexia-cachexia syndrome typically observed in cancer, infection with human immunodeficiency virus or chronic diseases rather than starvation, and that anx/anx mice could be considered a good model for the treatment and investigation of this condition. Keywords: genetic mutation analysis
2009-05-11 | GSE11426 | GEO
Project description:It has been recently shown that N-ras plays a preferential role in immune cell development and function; specifically: N-ras, but not H-ras or K-ras, could be activated at and signal from the Golgi membrane of immune cells following a low level TCR stimulus. The goal of our studies was to test the hypothesis that N-ras and H-ras played distinct roles in immune cells at the level of the transcriptome. First, we showed via mRNA expression profiling that there were over four hundred genes that were uniquely differentially regulated either by N-ras or H-ras, which provided strong evidence in favor of the hypothesis that N-ras and H-ras have distinct functions in immune cells. We next characterized the genes that were differentially regulated by N-ras in T cells following a low-level TCR stimulus. Of the large pool of candidate genes that were differentially regulated by N-ras downstream of TCR ligation, four genes were verified in qRT-PCR-based validation experiments as being differentially regulated by N-ras (Dntt, Slc9a6, Chst1, and Lars2). Finally, although there was little overlap between individual genes that were regulated by N-ras in unstimulated thymocytes and stimulated CD4+ T-cells, there was a nearly complete correspondence between the signaling pathways that were regulated by N-ras in these two immune cell types. Since we were interested primarily in genes that were differentially regulated by N-ras following a low-level TCR stimulus, our microarray data comparison was between data from TCR-stimulated, WT CD4+ T-cells and from TCR-stimulated, N-ras KO CD4+ T-cells. Genes that were differentially regulated in the comparison between stimulated N-ras KO CD4+ T-cells and unstimulated N-ras KO CD4+ T-cells, as well as those genes that were differentially regulated in the comparison between stimulated WT CD4+ T-cells and unstimulated WT CD4+ T-cells were excluded from this analysis. To determine if N-ras and H-ras regulate different sets of genes in thymocytes, a comparison was made between the set of genes that were differentially regulated by N-ras in the [WT] vs. [N-ras KO] comparison and the set of genes that were differentially regulated by H-ras in the [WT] vs. [H-ras KO] comparison. RNA was extracted from CD4+ T cell splenocytes isolated from 6-20 week old N-Ras KO and WT mice following growth in T cell growth media either with or without 1 microgram/milliliter ant-CD3 and anti-CD28 antibodies. RNA was extracted from thymocytes isolated directly from 6-20 week old N-Ras KO, H-Ras KO and WT mice.
2013-04-04 | E-GEOD-45739 | biostudies-arrayexpress