Day3 brown fat from wt compared to day3 from Gyk ko
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE4656 | GEO | 2007/03/11
SECONDARY ACCESSION(S): PRJNA95301
REPOSITORIES: GEO
Similar Datasets
Project description:Glycerol kinase (GK) is at the interface of fat and carbohydrate metabolism and has been implicated in insulin resistance and type 2 diabetes mellitus (T2DM). To define GK's role in insulin resistance, we examined gene expression in brown adipose tissue in a glycerol kinase (Gyk) knockout (KO) mouse model using microarray analysis. Global gene expression profiles of KO mice were distinct from wild type (WT) with 668 genes that were differentially expressed. These included genes involved in lipid metabolism, carbohydrate metabolism, insulin signaling, and insulin resistance. Real-Time (RT) PCR analysis confirmed the differential expression of selected genes involved in lipid and carbohydrate metabolism. PathwayAssist analysis confirmed direct and indirect connections between GK and genes in lipid metabolism, carbohydrate metabolism, insulin signaling, and insulin resistance. Network Component Analysis (NCA) showed that the transcription factors, peroxisome proliferator-activated receptor gamma (PPAR-γ), sterol regulatory element binding factor 1 (SREBP-1), SREBP-2, signal transducer and activator of transcription 3 (STAT3), STAT5, trans-acting transcription factor 1 (SP1), CCAAT/enhancer binding protein alpha (CEBP-α), cAMP responsive element binding protein 1 (CREB), glucocorticoid receptor (GR), and PPAR-α have altered activity in the KO mice. NCA also revealed the individual contribution of these transcription factors on the expression of genes altered in the microarray data. This study elucidates the transcription network of Gyk and further confirms a role for Gyk, a simple Mendelian disorder, in insulin resistance and T2DM, a common complex genetic disorder. Experiment Overall Design: 7 samples are analyzed; 3 wildtype and 4 KO. the WT samples are used as control and KO samples are used as the experimental group.
2007-11-22 | E-GEOD-4656 | biostudies-arrayexpress
Project description:Glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism with metabolic and neurologic crises. Liver shows the highest level of glycerol kinase (GK) activity in humans and mice. Absence of genotype-phenotype correlations in patients with GKD indicate the involvement of modifier genes, including other network partners. To understand the molecular pathogenesis of GKD, we performed microarray analysis on liver mRNA from neonatal glycerol kinase (Gyk) knockout (KO) and wild type (WT) mice. Unsupervised learning revealed the overall gene expression profile of the KO mice was different from that of WT. Real time PCR confirmed differences for selected genes. Functional gene enrichment analysis was used to find 56 increased and 37 decreased gene functional categories. Pathway Assist analysis identified changes in gene expression levels of genes involved in organic acid metabolism indicating that GK was part of the same metabolic network which correlates well with the patients with GKD having metabolic acidemia during their episodic crises. Network component analysis (NCA) showed that transcription factors SREBP-1c, ChREBP, HNF-4alpha, and PPAR-alpha, had increased activity in the Gyk KO mice compared with WT mice; while SREBP-2 was less active in the Gyk KO mice. These studies show that Gyk deletion causes alterations in gene expression of genes in several regulatory networks and is the first time NCA has been used to expand on microarray data from a mouse knockout model of a human disease. Keywords: Glycerol kinase (Gyk) knockout mouse; mouse model of human Glycerol Kinase Deficiency; Gyk KO versus WT liver expression analysis; Affymetrix mus 430 2.0 GeneChip
2005-12-22 | GSE3843 | GEO
Project description:Glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism with metabolic and neurologic crises. Liver shows the highest level of glycerol kinase (GK) activity in humans and mice. Absence of genotype-phenotype correlations in patients with GKD indicate the involvement of modifier genes, including other network partners. To understand the molecular pathogenesis of GKD, we performed microarray analysis on liver mRNA from neonatal glycerol kinase (Gyk) knockout (KO) and wild type (WT) mice. Unsupervised learning revealed the overall gene expression profile of the KO mice was different from that of WT. Real time PCR confirmed differences for selected genes. Functional gene enrichment analysis was used to find 56 increased and 37 decreased gene functional categories. Pathway Assist analysis identified changes in gene expression levels of genes involved in organic acid metabolism indicating that GK was part of the same metabolic network which correlates well with the patients with GKD having metabolic acidemia during their episodic crises. Network component analysis (NCA) showed that transcription factors SREBP-1c, ChREBP, HNF-4alpha, and PPAR-alpha, had increased activity in the Gyk KO mice compared with WT mice; while SREBP-2 was less active in the Gyk KO mice. These studies show that Gyk deletion causes alterations in gene expression of genes in several regulatory networks and is the first time NCA has been used to expand on microarray data from a mouse knockout model of a human disease. Male WT and KO mouse pups were sacrificed on day of life (dol) 3 and each liver was harvested. Total RNA from 4 KO and 4 WT livers was isolated individually. cDNA was synthesized from the poly(A)+ mRNA in the total RNA, Biotin-tagged and fragmented to an average strand length of 100 bases (range 35-200 bases). Ten µg of each cRNA was hybridized onto an Affymetrix mus 430 2.0 GeneChip to analyze differences in liver gene expression between KO and WT mice. Day of life three was chosen because the mice are phenotypically symptomatic with statistically different parameters for hypoglycemia, acidosis; low bicarbonate and decreased base excess. On day of life 2 they are not significantly different from wild type in all of these important clinical phenotypes.
2007-12-12 | E-GEOD-3843 | biostudies-arrayexpress
Project description:Amebiasis is caused by the protozoan parasite Entamoeba histolytica. Treatment options other than metronidazole and its derivatives are few, and their low efficacy against asymptomatic cyst carriers, and experimental evidence of resistance in vitro justify the discovery/repurposing campaign for new drugs against amebiasis. To better understand the role of glycerol metabolism in this parasite, we focused on characterizing two important enzymes, glycerol kinase (GK) and glycerol 3-phosphate dehydrogenase (G3PDH). Recombinant GK was biochemically characterized in detail, while G3PDH was not due to failure of protein expression and purification. GK revealed novel characteristics and unprecedented kinetic properties in reverse reaction. Gene silencing revealed that GK is essential for optimum growth, whereas G3PDH is not. Gene silencing of G3PDH caused upregulated GK expression, while that of GK resulted in upregulation of antioxidant enzymes as shown by RNA-seq analysis. Although the precise molecular link between GK and the upregulation of antioxidant enzymes was not demonstrated, the observed increase in antioxidant enzyme expression upon GK gene silencing suggests a potential connection between GK and the cellular response to oxidative stress. Together, these results provide the first direct evidence of the biological importance and coordinated regulation of the glycerol metabolic pathways for proliferation and antioxidative defense in E. histolytica, justifying the exploitation of these enzymes as future drug targets.
2023-08-14 | GSE240436 | GEO
Project description:Insulin resistance and Type 2 Diabetes Mellitus (T2DM) are associated with increased adipocyte size, altered secretory pattern and decreased differentiation of preadipocytes. To identify the underlying molecular processes in preadipocytes of T2DM patients that are a characteristic of the development of T2DM, preadipocyte cell cultures were prepared from subcutaneous fat biopsies of T2DM patients and compared with age- and BMI matched control subjects. Gene expression profiling showed changed expression of transcription factors involved in adipogenesis and in extracellular matrix remodeling, actin cytoskeleton and integrin signaling genes, which indicated decreased capacity to differentiate. Additionally, genes involved in insulin signaling and lipid metabolism were down-regulated, and inflammation/apoptosis was up-regulated in T2DM preadipocytes. The down-regulation of genes involved in differentiation can provide a molecular basis for the reduced adipogenesis of preadipocytes of T2DM subjects, leading to reduced formation of adipocytes in subcutaneous fat depots, and ultimately leading to ectopic fat storage. 7 T2DM preadipocyte samples and 9 age- and BMI-matched control samples were hybridized using 70-mer oligonucleotide microarrays. Samples were labeled with either Cy3 or Cy5. A total of 20 arrays were used including dye swop. Per array, a T2DM sample was hybridized with a control sample of the same gender and matched based on age and BMI. To ensure hybridization of two samples with the same gender, three T2DM (5064, 5128, 5395) and one control sample (5616) were used twice and listed as technical replicates.
2010-05-16 | E-GEOD-15790 | biostudies-arrayexpress
Project description:Insulin resistance and Type 2 Diabetes Mellitus (T2DM) are associated with increased adipocyte size, altered secretory pattern and decreased differentiation of preadipocytes. To identify the underlying molecular processes in preadipocytes of T2DM patients that are a characteristic of the development of T2DM, preadipocyte cell cultures were prepared from subcutaneous fat biopsies of T2DM patients and compared with age- and BMI matched control subjects. Gene expression profiling showed changed expression of transcription factors involved in adipogenesis and in extracellular matrix remodeling, actin cytoskeleton and integrin signaling genes, which indicated decreased capacity to differentiate. Additionally, genes involved in insulin signaling and lipid metabolism were down-regulated, and inflammation/apoptosis was up-regulated in T2DM preadipocytes. The down-regulation of genes involved in differentiation can provide a molecular basis for the reduced adipogenesis of preadipocytes of T2DM subjects, leading to reduced formation of adipocytes in subcutaneous fat depots, and ultimately leading to ectopic fat storage.
2009-12-31 | GSE15790 | GEO
Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration. Insulin-treated T2DM subjects before and after 52 weeks of exercise training (T2DM_0 and T2DM_52), normoglycemic controls (NGT) and pre-diabetes subjects (IGT) and were selected. RNA was extracted from skeletal muscle biopsies and hybridized on Affymetrix microarrays.
2010-11-29 | E-GEOD-19420 | biostudies-arrayexpress
Project description:The Goto-Kakizak (GK) rat, a nonobese animal model of Type 2 diabetes (T2D), were developed by repeated inbreeding of glucose-intolerent individuals selected from Wistar rats. During their development, GK rats suffer from reduced beta-cell mass and insulin resistance spontaneously (T2D phenotype), which are supposed to be caused by loci holding different genotypes between GK and Wistar rats. This array CGH experiment can detect loci which show different copy numbers (genotype) between GK and Wistar rats. These loci serve as a valuable repository for mining candidates contributing to the pathogenesis of T2D.
2010-12-31 | GSE21387 | GEO
Project description:The goals and objectives: To study Type 2 diabetes progression and the development of insulin resistance in two animal models with and without a high fat diet superimposed on these models. Background: Diabetes is a systemic metabolic imbalance involving multiple tissues/organs, and an early hallmark feature of this disease state is insulin resistance. Multifactorial interactions of genetics, prenatal environmental factors (fetal programming) and postnatal environmental factors (nutrition and activity) likely contribute to the diabetic phenotype.Animal models can serve as a valuable tool for studying diabetes disease progression and for identifying useful biomarkers of type 2 diabetes. Several inbred rodent models are available for diabetes related studies. The GK rat is an obvious choice among available inbred models as the genetic basis for this inheritable form of diabetes is polygenic (5), unlike most other inbred rodent models that exhibit single gene defects. Many of the characteristics of the GK rat mirror human diabetes (hyperglycemia, glucose intolerance, insulin resistance), although hyperlipidemia does not appear to be prominent in the GK rat. Due to its polygenic mode of inheritance and 100% penetrance, the GK rat may be a useful model for human diabetes. Induced animal models can also be useful in diabetes studies. One such model is metabolic syndrome resulting from experimentally induced fetal programming (produced by maternal malnutrition or by exposure to corticosteroids in the third trimester). Both in humans and animals, accumulating evidence suggests that alterations in the human fetal environment can result in permanent physiologic changes that manifest as increased incidence of adult onset pathology. Numerous epidemiological studies have forged a strong link between low birth weight and the development of metabolic syndrome in adulthood. From such observations has arisen the concept of âfetal programmingâ whereby exposure to some factor(s) during crucial stages in development can permanently alter or âresetâ physiologic/metabolic functions. In the rat, exposure to corticosteroids during a âwindowâ in third trimester gestation (CS programming) results in fetal growth retardation and insulin resistance in adult offspring. Genetic factors play a primarily role in the etiology of diabetes in the GK rat, whereas fetal environmental factors are causative in CS programming. (It should be noted that although altered fetal environmental effects, most likely stemming from maternal hyperglycemia, have been implicated to play some role in the decreased pancreatic B cell mass in GK rats, these effects occur earlier in gestation and therefore differ from programming by CS in late gestation.) A comparison of the development of insulin resistance in the GK rat with development in the CS programmed rat will provide insight into genetic and fetal environmental factors in disease development. Superimposing dietary alterations (i.e., high fat feeding) (11) on both animal models may aid in the dissection of multiple interacting factors (genetic, fetal environmental factors, postnatal environmental factors) on the development and progression of insulin resistance and type 2 diabetes. Such studies may also aid in the identification of useful biomarkers for insulin resistance and type 2 diabetes in humans. Proposed research: Experiments are designed to study disease progression and the development of insulin resistance in two animal models: the GK rat and the CS programmed rat, with and without a high fat diet superimposed on these models. Animals will be maintained in our facility from weaning (GK rats) or birth (CS programmed - WKY), and body weights taken weekly. Appropriate diets (normal or high fat) will be introduced at weaning. Groups of animals (N=6) will be sacrificed at 5 different ages: 4, 8, 12, 16, and 20 weeks. Plasma samples will be analyzed for markers of hyperglycemia, hyperinsulinemia, dyslipidimia, and for selected other hormonal factors which may contribute to disease etiology (adiponectin, leptin, corticosterone). At sacrifice, muscle is harvested, flash-frozen in liquid nitrogen, and warehoused in our tissue collection maintained at - 80 degrees C for this and possible future work. Study will initially focus on examination of selected molecular markers of insulin resistance at the mRNA level in rat abdominal fat (PEPCK, IRS-1). Experiment Overall Design: The study contains: 50 adipose tissue samples from GK (GotoKakizake) rats and 51 adipose tissue samples from WKY (WistarKyoto) rats feeded with normal diet (ND) and high fat diet (HFD) and sacrificed at 5 different ages: 4, 8, 12, 16, and 20 weeks. So, each time point contains 5 GK samples with ND, 5 GK samples with HFD, 5 WKY samples with ND and 5 WKY samples with HFD.
2009-11-10 | E-GEOD-13268 | biostudies-arrayexpress
Project description:The goals and objectives: To study Type 2 diabetes progression and the development of insulin resistance in two animal models with and without a high fat diet superimposed on these models. Background: Diabetes is a systemic metabolic imbalance involving multiple tissues/organs, and an early hallmark feature of this disease state is insulin resistance. Multifactorial interactions of genetics, prenatal environmental factors (fetal programming) and postnatal environmental factors (nutrition and activity) likely contribute to the diabetic phenotype.Animal models can serve as a valuable tool for studying diabetes disease progression and for identifying useful biomarkers of type 2 diabetes. Several inbred rodent models are available for diabetes related studies. The GK rat is an obvious choice among available inbred models as the genetic basis for this inheritable form of diabetes is polygenic (5), unlike most other inbred rodent models that exhibit single gene defects. Many of the characteristics of the GK rat mirror human diabetes (hyperglycemia, glucose intolerance, insulin resistance), although hyperlipidemia does not appear to be prominent in the GK rat. Due to its polygenic mode of inheritance and 100% penetrance, the GK rat may be a useful model for human diabetes. Induced animal models can also be useful in diabetes studies. One such model is metabolic syndrome resulting from experimentally induced fetal programming (produced by maternal malnutrition or by exposure to corticosteroids in the third trimester). Both in humans and animals, accumulating evidence suggests that alterations in the human fetal environment can result in permanent physiologic changes that manifest as increased incidence of adult onset pathology. Numerous epidemiological studies have forged a strong link between low birth weight and the development of metabolic syndrome in adulthood. From such observations has arisen the concept of âfetal programmingâ whereby exposure to some factor(s) during crucial stages in development can permanently alter or âresetâ physiologic/metabolic functions. In the rat, exposure to corticosteroids during a âwindowâ in third trimester gestation (CS programming) results in fetal growth retardation and insulin resistance in adult offspring. Genetic factors play a primarily role in the etiology of diabetes in the GK rat, whereas fetal environmental factors are causative in CS programming. (It should be noted that although altered fetal environmental effects, most likely stemming from maternal hyperglycemia, have been implicated to play some role in the decreased pancreatic B cell mass in GK rats, these effects occur earlier in gestation and therefore differ from programming by CS in late gestation.) A comparison of the development of insulin resistance in the GK rat with development in the CS programmed rat will provide insight into genetic and fetal environmental factors in disease development. Superimposing dietary alterations (i.e., high fat feeding) (11) on both animal models may aid in the dissection of multiple interacting factors (genetic, fetal environmental factors, postnatal environmental factors) on the development and progression of insulin resistance and type 2 diabetes. Such studies may also aid in the identification of useful biomarkers for insulin resistance and type 2 diabetes in humans. Proposed research: Experiments are designed to study disease progression and the development of insulin resistance in two animal models: the GK rat and the CS programmed rat, with and without a high fat diet superimposed on these models. Animals will be maintained in our facility from weaning (GK rats) or birth (CS programmed - WKY), and body weights taken weekly. Appropriate diets (normal or high fat) will be introduced at weaning. Groups of animals (N=6) will be sacrificed at 5 different ages: 4, 8, 12, 16, and 20 weeks. Plasma samples will be analyzed for markers of hyperglycemia, hyperinsulinemia, dyslipidimia, and for selected other hormonal factors which may contribute to disease etiology (adiponectin, leptin, corticosterone). At sacrifice, muscle is harvested, flash-frozen in liquid nitrogen, and warehoused in our tissue collection maintained at - 80 degrees C for this and possible future work. Study will initially focus on examination of selected molecular markers of insulin resistance at the mRNA level in rat liver (PEPCK, PDK4). Experiment Overall Design: The study contains: 50 liver samples from GK (GotoKakizake) rats and 51 liver sample from WKY (WistarKyoto) rats feeded with normal diet (ND) and high fat diet (HFD) and sacrificed at 5 different ages: 4, 8, 12, 16, and 20 weeks. So, each time point contains 5 GK samples with ND, 5 GK samples with HFD, 5 WKY samples with ND and 5 WKY samples with HFD.
2009-11-10 | E-GEOD-13270 | biostudies-arrayexpress