Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiles in heterogeneous stock rats that differ in glucose tolerance

ABSTRACT: Using heterogeneous stock (HS) rats, we have identified a region on rat chromosome 1 that maps multiple diabetic traits. We sought to use global expression analysis to determine if genes within this region are differentially expressed between HS rats with normal glucose tolerance and those with glucose intolerance HS rats were euthanized at 17 weeks of age and liver was immediately frozen in liquid nitrogen. RNA was extracted from liver of 23 HS rats with glucose intolerance and 23 HS rats with normal glucose. The Affymetrix 230_2 array was used to probe transcript abundance levels.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Leah Solberg Woods

PROVIDER: E-GEOD-54935 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Metabolic syndrome is associated with chronic low-grade inflammation which plays an important role in the pathogenesis of insulin resistance. Salsalate is a non-steroidal anti-inflammatory drug that reduces levels of inflammatory mediators. In the current study, we tested the effects of salsalate on inflammation, oxidative stress and metabolic disturbances in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 15-month-old male transgenic SHR-CRP rats with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without salsalate. In a similar fashion, we studied a group of nontransgenic SHR treated with salsalate and an untreated group of nontransgenic SHR controls. Parameters of inflammation and glucose and lipid metabolism were measured using standard methods. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that salsalate treatment decreased circulating levels of inflammatory markers TNFï¡ and MCP-1 and levels of human CRP as well as reduced levels of lipopreroxidation products in the liver and kidney cortex. Lipidomics analysis of eicosanoids confirmed anti-inflammatory effects of salsalate. Reduced inflammation and oxidative stress were associated with increased sensitivity of skeletal muscles to insulin action and greater tolerance to glucose and with reduced glucose oxidation and incorporation in brown adipose tissue (BAT). In SHR controls with no CRP-induced inflammation, salsalate treatment was associated with reduced body weight, lower levels of serum free fatty acids, total and HDL cholesterol and increased palmitate oxidation and incorporation in BAT. Salsalate regulated lipid metabolism by affecting expression of genes from PPAR signaling pathways and inflammation by affecting expression from MAPK signaling and NOD-like receptor signaling pathways. In summary, in the presence of high levels of human CRP, salsalate reduced inflammation which was associated with reduced oxidative stress and amelioration of insulin resistance in skeletal muscle and glucose intolerance while in non-transgenic SHR rats, salsalate ameliorated dyslipidemia and activated BAT. Thus it is possible that amelioration of insulin resistance and glucose intolerance in SHR-CRP rats treated with salsalate is due to reduced inflammation while amelioration of dyslipidemia in SHR rats treated with salsalate is due to activation of BAT. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

Project description:The etiology of trauma-hemorrhage shock-induced acute lung injury has been difficult to elucidate due, at least in part, to the inability of in vivo studies to separate the non-injurious pulmonary effects of trauma-hemorrhage from the tissue injurious ones. To circumvent this in vivo limitation, we utilized a model of trauma-hemorrhagic shock (T/HS) in which T/HS-lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the non-injurious systemic response to T/HS by comparing the pulmonary molecular response of rats subjected to T/HS which did and did not develop lung injury as well as to non-shocked rats. Utilizing high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 hours after the end of the shock or sham-shock period, 139 of the 8,799 assessed genes were differentially expressed. Experiment Overall Design: Four groups of rats (n=3) were studied in order to identify changes in pulmonary gene expression associated with T/HS, both in the presence and absence of lung injury. These included trauma-sham shock (T/SS) rats which had a laparotomy (trauma) but were not subjected to hemorrhagic shock. These rats had no lung injury and served as controls for rats which were subjected to T/HS (laparotomy plus 90 min of shock) and had lung injury. Differences in gene expression between these two groups would represent both the effects of hemorrhagic shock as well as lung injury. To distinguish the gene response of hemorrhagic shock from the gene response associated with lung injury, gene expression was also compared between T/HS rats (hemorrhage and lung injury) and rats subjected to T/HS plus lymph duct ligation (T/HS-LDL), since the T/HS-LDL rats experienced hemorrhagic shock but had no measurable lung injury. Lastly, to identify hemorrhagic shock- modified genes, the pulmonary gene response of T/HS-LDL (hemorrhage without lung injury) were compared to rats subjected to T/SS plus LDL (no hemorrhage or lung injury). Three hours after the end of the 90 min shock or sham-shock period (i.e. 4.5 hrs after the induction of T/HS), the rats were sacrificed and specimens harvested for genechip analysis and histology.

Project description:High-protein diets are known to reduce adiposity in the context of high carbohydrate and Western diets. However, few studies have investigated the specific high-protein effect on lipogenesis induced by a high-sucrose (HS) diet or fat deposition induced by high-fat feeding. We aimed to determine the effects of high protein intake on the development of fat deposition and partitioning in response to high-fat and/or HS feeding. A total of thirty adult male Wistar rats were assigned to one of the six dietary regimens with low and high protein, sucrose and fat contents for 5 weeks. Body weight (BW) and food intake were measured weekly. Oral glucose tolerance tests and meal tolerance tests were performed after 4th and 5th weeks of the regimen, respectively. At the end of the study, the rats were killed 2 h after ingestion of a calibrated meal. Blood, tissues and organs were collected for analysis of circulating metabolites and hormones, body composition and mRNA expression in the liver and adipose tissues. No changes were observed in cumulative energy intake and BW gain after 5 weeks of dietary treatment. However, high-protein diets reduced by 20 % the adiposity gain induced by HS and high-sucrose high-fat (HS-HF) diets. Gene expression and transcriptomic analysis suggested that high protein intake reduced liver capacity for lipogenesis by reducing mRNA expressions of fatty acid synthase (fasn), acetyl-CoA carboxylase a and b (Acaca and Acacb) and sterol regulatory element binding transcription factor 1c (Srebf-1c). Moreover, ketogenesis, as indicated by plasma β-hydroxybutyrate levels, was higher in HS-HF-fed mice that were also fed high protein levels. Taken together, these results suggest that high-protein diets may reduce adiposity by inhibiting lipogenesis and stimulating ketogenesis in the liver. Adult male Wistar rats were fed diets with varying amounts of protein, carbohydrates and fat for 5 weeks. At the end of the experiment, rats were killed and tanscriptome analysis was performed on pooled liver samples.

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Gene expression profiles in heterogeneous stock rats that differ in glucose tolerance

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