Through employing a comparative transcriptomics approach, we identified IRF1 as differentiatlly regulated between primary and in vitro derived genetically matched adipocytes.
Activation of IRF1 in Human Adipocytes Leads to Phenotypes Associated with Metabolic Disease.
Specimen part
View SamplesWe assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity.
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms.
Sex
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Genetic architecture of insulin resistance in the mouse.
Sex, Age, Specimen part
View SamplesIdentify genes in the gonadal adipose tissue whose expression is under genetic regulation in the Hybrid Mouse Diversity Panel (HMDP). The HMDP comprises classical inbred and recombinant inbred wild type mice. The RMA values of genes were used for genome wide association as described in Parks et al Cell Metabolism 2015. These data are used to identify candidate genes at loci associated with obesity and dietary responsiveness.
Genetic architecture of insulin resistance in the mouse.
Sex, Age, Specimen part
View SamplesIdentify genes in the liver whose expression is under genetic regulation in the Hybrid Mouse Diversity Panel (HMDP). The HMDP comprises classical inbred and recombinant inbred wild type mice. The RMA values of genes were used for genome wide association as described in Parks et al Cell Metabolism 2015. These data are used to identify candidate genes at loci associated with obesity and dietary responsiveness.
Genetic architecture of insulin resistance in the mouse.
Sex, Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Programming human pluripotent stem cells into white and brown adipocytes.
Specimen part, Disease
View SamplesThe utility of human pluripotent stem cells as a tool for understanding disease and as a renewable source of cells for transplantation therapies is dependent on efficient differentiation protocols that convert these cells into relevant adult cell types. Here we report the robust and efficient differentiation of human pluripotent stem cells into adipocytes. We found that inducible expression of PPARG2 in pluripotent stem cell-derived mesenchymal progenitor cells programmed their development towards an adipocyte cell fate. Using this approach, multiple human pluripotent cell lines were differentiated into adipocytes with efficiencies of 85% to 90%. These pluripotent stem cell-derived adipocytes retained their identity independent of transgene expression, could be maintained in culture for several weeks, expressed mature markers, and exhibited mature functional properties such as lipid catabolism in response to a beta-adrenergic stimulus. Global transcriptional and lipid metabolomic analyses further confirmed the identity and maturity of these pluripotent stem cell-derived adipocytes.
Programming human pluripotent stem cells into white and brown adipocytes.
Specimen part
View SamplesType 1 diabetes is a multigenic disease caused by T-cell mediated destruction of the insulin producing -cells. Although conventional (targeted) approaches of identifying causative genes have advanced our knowledge of this disease, many questions remain unanswered. Using a whole molecular systems study, we unraveled the genes/molecular pathways that are altered in CD4 T-cells from young NOD mice prior to insulitis (lymphocytic infiltration into the pancreas). Many of the CD4 T-cell altered genes lie within known diabetes susceptibility regions (Idd), including several genes in the diabetes resistance region Idd13 and two genes (Khdrbs1 and Ptp4a2) in the CD4 T-cell diabetogenic activity region Idd9/11. Alterations involved apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks), inflammation and cell signaling/activation (predominant at 3 weeks), and innate and adaptive immune responses (predominant at 4 weeks). We identified several factors that may regulate these abnormalities: IRF-1, HNF4A, TP53, BCL2L1 (lies within Idd13), IFNG, IL4, IL15, and prostaglandin E2, which were common to all 3 ages; AR and IL6 to 2 and 4 weeks; and Interferon (IFN-I) and IRF-7 to 3 and 4 weeks. Others were unique to the various ages (e. g. MYC, JUN, and APP to 2 weeks; TNF, TGFB1, NFKB, ERK, and p38MAPK to 3 weeks; and IL12 and STAT4 to 4 weeks). Our data suggest that diabetes resistance genes in Idd13 and Idd9/11, and BCL2L1, IL6-AR and IFNG-IRF-1-IFN-I/IRF-7-IL12 pathways play an important role in CD4 T-cells in the early pathogenesis of autoimmune diabetes. Thus, the alternative approach of investigation at the molecular systems level has captured new information, which combined with validation studies, offers the opportunity to test hypotheses on the role played by the genes/molecular pathways identified in this study, to understand better the mechanisms of autoimmune diabetes in CD4 T-cells, and to develop new therapeutic strategies for the disease.
Molecular pathway alterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phase of autoimmune diabetes.
Age, Specimen part
View SamplesIslet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse a model for human type 1 diabetes (T1DM). The molecular events leading to insulitis are poorly understood. Since TIDM is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease.
Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes.
Age, Specimen part
View SamplesHypoxia plays a key pathogenic role in the outcome of many pathologic conditions. To elucidate how organisms successfully adapt to hypoxia, a population of Drosophila melanogaster was generated, through an iterative selection process, that is able to complete its lifecycle at 4% O2, a level lethal to the starting parental population. Transcriptomic analysis of flies adapted for >200 generations was performed to identify pathways and processes that contribute to the adapted phenotype, comparing gene expression of three developmental stages with generation-matched control flies. A third group was included, hypoxia-adapted flies reverted to 21% O2 for five generations, to address the relative contributions of genetics and hypoxic environment to the gene expression differences. We identified the largest number of expression differences in 0.5-3 hr post-eclosion adult flies that were hypoxia-adapted and maintained in 4% O2, and found evidence that changes in Wnt signaling contribute to hypoxia tolerance in flies.
Wnt pathway activation increases hypoxia tolerance during development.
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