Project description:Gene expression data was generated in BN and SHR rats to correlate gene expression differences with CpG methylation differences detected between the strains by whole-genome bisulfite sequencing.
Project description:Abnormalities in metabolism of energetic substrates may play a role in progression of chronic heart failure (HF). The goal of the study was to examine the extent and mechanisms of metabolic alterations in rat model of chronic HF due to volume overload. Volume overload was induced in 3 months old male Wistar rats by aorto-caval fistula. In the phase of symptomatic HF (after 21 weeks), we performed myocardial gene expression analysis. Cardiac tissue gene expression analysis showed downregulation of enzymes of respiratory cycle, mitochondrial fatty acid (FA) oxidation and attenuated expression of proteins responsible for FA translocation/transport (CD36/FAT, FABP3, FATP-1). Simultaneously, we performed gene expression analysis of fat tissue.
Project description:Resistin has been originally identified as an adipokine that links obesity to insulin resistance in mice. In our previous studies in spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin (Retn) transgene specifically in adipose tissue (SHR-Retn), we observed an increased lipolysis and serum free fatty acids, ectopic fat accumulation in muscles and insulin resistance. Recently, brown adipose tissue (BAT) has been suggested to play an important role in the pathogenesis of metabolic disturbances by its ability to dissipate energy excess. In the current study, we analyzed autocrine effects of transgenic resistin on BAT glucose and lipid metabolism and mitochondrial function in the SHR-Retn versus nontransgenic SHR controls. We observed that interscapular BAT isolated from SHR-Retn transgenic rats when compared to SHR controls showed a lower relative weight, significantly reduced both basal and insulin stimulated incorporation of palmitate into BAT lipids, and significantly decreased palmitate oxidation and glucose oxidation. In addition, in vivo microPET imaging revealed significantly reduced 18F-FDG uptake in BAT induced by exposure to cold in SHR-Retn versus control SHR. Gene expression profiles identified differentially expressed genes involved in skeletal muscle and connective tissue developmental and inflammation, as well as MAPK and insulin signaling. These results provide compelling evidence that autocrine effects of resisitin in BAT play an important role in the pathogenesis of insulin resistance in the rat.
Project description:Inflammation, oxidative and dicarbonyl stress play important roles in the pathophysiology of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver, however, its “pleiotropic“ effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP). In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL6 while levels of human CRP remained unchanged and metformin also significantly reduced oxidative stress (levels of conjugated dienes and TBARS) in the liver while no significant effects were observed in SHR control rats. In addition, in the presence of high human CRP, metformin reduced methylglyoxal levels in left ventricles but not in kidneys. Finally, metformin treatment reduced adipose tissue lipolysis. Possible molecular mechanisms of metformin action studied by gene expression profiling in the liver revealed deregulated genes from inflammatory, insulin signaling, AMP-activated protein kinase (AMPK) signaling and gluconeogenesis pathways. It can be concluded that in the presence of high levels of human CRP metformin protects against inflammation, oxidative and dicarbonyl stress in the heart and ameliorates insulin resistance and dyslipidemia.
Project description:Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate (DMF), exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances.
Project description:Histone modifications are epigenetic marks that play fundamental roles in many biological processes including the control of chromatin-mediated regulation of gene expression. To begin to understand the impact of natural variation on histone methylation levels we generated and quantified large-scale genome-wide ChIP-seq data in a panel of rat recombinant inbred strains and their parental progenitors. Linkage analysis identified hundreds of cis- and trans-acting loci responsible for quantitative differences in histone trimethyl-lysine levels in left ventricular heart and liver tissues. We assessed the association of histone methylation and gene expression levels by generating deep RNA-seq profiles across the segregating population. Among the main findings, causal modelling of DNA variation together with histone methylation and gene expression levels enhanced the prediction of gene expression traits (eQTLs) by ~20%. Moreover, allele specific differences of histone trimethyl-lysine levels at alternative promoters were associated with differential usage of transcriptional start sites. Our data suggest that genetic variation has widespread impact on histone modifications. The highly adapted interplay between DNA variation and chromatin structure has consequences on gene and isoform expression as direct functional outcome and demonstrated new avenues to find novel genotype Ð phenotype relationships. NOTE: Additional processed data files were added to this experiment on the 24th April 2014. They are in the zip archive E-MTAB-1102.additional.1.zip which is available under the 'Click to browse all available files' link.
Project description:The spontaneously hypertensive rat (SHR) is the most widely used model of essential hypertension and is predisposed to left ventricular hypertrophy, myocardial fibrosis, and metabolic disturbances. Recently, a quantitative trait locus (QTL) influencing blood pressure, left ventricular mass and heart interstitial fibrosis was genetically isolated within 788 kb on chromosome 8 segment of SHR-PD5 congenic strain that contains only 7 genes, including mutant Plzf (promyelocytic leukemia zinc finger) gene. To identify Plzf as a quantitative trait gene, we targeted Plzf in the SHR using the TALEN technique and obtained SHR line harboring mutant Plzf gene with a premature stop codon at position of amino acid 58. The Plzf mutant allele is semi-lethal since approximately 95% of newborn homozygous animals die perinatally due to multiple developmental abnormalities. Heterozygous rats were grossly normal and were used for metabolic and hemodynamic analyses. SHR-Plzf+/- heterozygotes versus SHR wild type controls exhibited reduced body weight and relative weight of epididymal fat, lower serum and liver triglycerides and cholesterol and better glucose tolerance. In addition, SHR-Plzf+/- rats exhibited significantly increased sensitivity of adipose and muscle tissue to insulin action when compared to wild type controls. Blood pressure was comparable in SHR versus SHR-Plzf+/-, however, there was significant amelioration of cardiomyocyte hypertrophy and cardiac fibrosis in SHR-Plzf+/- rats. Gene expression profiles in the liver and expression of selected genes in the heart revealed differentially expressed genes playing a role in metabolic pathways, PPAR signaling, and cell cycle regulation. These results provide evidence for an important role of Plzf in regulation of metabolic and cardiac traits in the rat and suggest a cross-talk between cell cycle regulators, metabolism, cardiac hypertrophy and fibrosis.