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Protein sets define disease states and predict in vivo effects of drug treatment [heart]

ABSTRACT: Gaining understanding of common complex diseases and their treatments are the main drivers for life sciences. As we show here, comprehensive protein set analyses offer new opportunities to decipher functional molecular networks of diseases and assess the efficacy and side-effects of treatments in vivo. Using mass spectrometry, we quantitatively detected several thousands of proteins and observed significant changes in protein pathways that were (dys-) regulated in diet-induced obesity mice. Analysis of the expression and post-translational modifications of proteins in various peripheral metabolic target tissues including adipose, heart, and liver tissue generated functional insights in the regulation of cell and tissue homeostasis during high-fat diet feeding and medication with two antidiabetic compounds. Protein set analyses singled out pathways for functional characterization, and indicated, for example, early-on potential cardiovascular complication of the diabetes drug rosiglitazone. In vivo protein set detection can provide new avenues for monitoring complex disease processes, and for evaluating preclinical drug candidates. Male C57BL/6 mice (age 6 wks) were fed for 12 weeks with high-fat diet (HFD) and than distributed into 3 groups. Mice were then fed over 3 weeks with HFD without compound ('HFD'), HFD with 4 mg/kg/d rosiglitazone ('HFD_RSG') or with 100 mg/kg/d amorfrutin 1 ('HFD_A1'). Finally, HEART tissue was harvested and RNA extracted. --> 3-4 biological replicates (2 mice per each replicate, RNA of 2 mice always pooled).

ORGANISM(S): Mus musculus

SUBMITTER: Christopher Weidner

PROVIDER: E-GEOD-38852 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Protein sets define disease states and predict in vivo effects of drug treatment.

Meierhofer David D Weidner Christopher C Hartmann Ludger L Mayr Johannes A JA Han Chung-Ting CT Schroeder Frank C FC Sauer Sascha S

Molecular & cellular proteomics : MCP 20130411 7

Gaining understanding of common complex diseases and their treatments are the main drivers for life sciences. As we show here, comprehensive protein set analyses offer new opportunities to decipher functional molecular networks of diseases and assess the efficacy and side-effects of treatments in vivo. Using mass spectrometry, we quantitatively detected several thousands of proteins and observed significant changes in protein pathways that were (dys-) regulated in diet-induced obesity mice. Anal ...[more]

PMID: 23579186

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Project description:Gaining understanding of common complex diseases and their treatments are the main drivers for life sciences. As we show here, comprehensive protein set analyses offer new opportunities to decipher functional molecular networks of diseases and assess the efficacy and side-effects of treatments in vivo. Using mass spectrometry, we quantitatively detected several thousands of proteins and observed significant changes in protein pathways that were (dys-) regulated in diet-induced obesity mice. Analysis of the expression and post-translational modifications of proteins in various peripheral metabolic target tissues including adipose, heart, and liver tissue generated functional insights in the regulation of cell and tissue homeostasis during high-fat diet feeding and medication with two antidiabetic compounds. Protein set analyses singled out pathways for functional characterization, and indicated, for example, early-on potential cardiovascular complication of the diabetes drug rosiglitazone. In vivo protein set detection can provide new avenues for monitoring complex disease processes, and for evaluating preclinical drug candidates. Male C57BL/6 mice (age 6 wks) were fed for 12 weeks with high-fat diet (HFD) and than distributed into 3 groups. Mice were than fed over 3 weeks with HFD without compound ('HFD'), HFD with 4 mg/kg/d rosiglitazone ('HFD_RSG') or with 100 mg/kg/d amorfrutin 1 ('HFD_A1'). In parallel [GSE38854; Liver B], mice were fed for 15 weeks with low-fat diet (LFD) as healthy control subjects. In addition, a group of mice was treated with 37 mg/kg/d amorfrutin 1 during the whole 15 weeks of HFD feeding ('HFD+A1prev'). Finally, LIVER tissue was harvested and RNA extracted. --> 3-4 biological replicates (2 mice per each replicate, RNA of 2 mice always pooled). liver_HFD_*A and _*B samples are from the same biological source material, but the cRNA preparation and hybridization to Illumina arrays were performed at different days (i.e. technical repeats).

Project description:Gaining understanding of common complex diseases and their treatments are the main drivers for life sciences. As we show here, comprehensive protein set analyses offer new opportunities to decipher functional molecular networks of diseases and assess the efficacy and side-effects of treatments in vivo. Using mass spectrometry, we quantitatively detected several thousands of proteins and observed significant changes in protein pathways that were (dys-) regulated in diet-induced obesity mice. Analysis of the expression and post-translational modifications of proteins in various peripheral metabolic target tissues including adipose, heart, and liver tissue generated functional insights in the regulation of cell and tissue homeostasis during high-fat diet feeding and medication with two antidiabetic compounds. Protein set analyses singled out pathways for functional characterization, and indicated, for example, early-on potential cardiovascular complication of the diabetes drug rosiglitazone. In vivo protein set detection can provide new avenues for monitoring complex disease processes, and for evaluating preclinical drug candidates. Male C57BL/6 mice (age 6 wks) were fed for 12 weeks with high-fat diet (HFD) and than distributed into 3 groups. Mice were than fed over 3 weeks with HFD without compound ('HFD'), HFD with 4 mg/kg/d rosiglitazone ('HFD_RSG') or with 100 mg/kg/d amorfrutin 1 ('HFD_A1') [GSE38853; Liver A]. In parallel, mice were fed for 15 weeks with low-fat diet (LFD) as healthy control subjects. In addition, a group of mice was treated with 37 mg/kg/d amorfrutin 1 during the whole 15 weeks of HFD feeding ('HFD+A1prev'). Finally, LIVER tissue was harvested and RNA extracted. --> 3-4 biological replicates (2 mice per each replicate, RNA of 2 mice always pooled). liver_HFD_*A and _*B samples are from the same biological source material, but the cRNA preparation and hybridization to Illumina arrays were performed at different days (i.e. technical repeats).

Project description:Background: Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of pro-inflammatory mediators, including TNFalpha and IL-6. Recent data suggest that during diet-induced obesity the phenotype of adipose-resident macrophages changes from alternatively activated macrophages towards a more classical and pro-inflammatory phenotype. Here, we explore the effect of PPARγ-activation on obesity-induced inflammation in 129SV mice fed a high fat diet for 20 weeks. High fat feeding increased bodyweight gain, adipose tissue mass and liver triglycerides. Rosiglitazone treatment further increased adipose mass, reduced liver triglycerides and changed adipose tissue morphology towards smaller adipocytes. Surprisingly, rosiglitazone markedly increased the number of macrophages in adipose tissue, as shown by immunohistochemical analysis and quantification of macrophage marker genes CD68 and F4/80+. In adipose tissue, markers for classically activated macrophages including IL-18 were down regulated whereas markers characteristic for alternatively activated macrophages (Arginase 1, IL-10) were up regulated by rosiglitazone. Importantly, conditioned media from rosiglitazone-treated alternatively activated macrophages neutralized the inhibitory effect of macrophages on 3T3-L1 adipocyte differentiation, suggesting that alternatively activated macrophages may be involved in mediating the effects of rosiglitazone on adipose tissue morphology and mass. Our results suggest that short term rosiglitazone treatment increases infiltration of alternatively activated macrophages in adipose tissue. The alternatively activated macrophages might play a role in PPARγ-dependent expansion and remodeling of adipose tissue. Keywords: metabolic state analysis Pure bred wild-type (129S1/SvImJ) male mice received a low fat diet or high fat diet for 21 weeks, providing 10 or 45% energy percent in the form of triglycerides (D12450B or D12451, Research Diets, New Brunswick, USA). The lard component in these diets was replaced by palm oil. In the last week of diet intervention, half of the mice receiving the HFD were switched to HFD supplemented with Rosiglitazone (0.01 % wt/wt). Animals were sacrificed in the fed state. Epididymal adipose tissue was excised and frozen in liquid nitrogen. Pooled RNA samples from 5 mice per experimental group were used for microarray analysis. Samples were hybridized on Affymetrix GeneChip Mouse Genome 430-2.0 plus arrays. Five microgram total RNA was labelled according to the Affymetrix One-cycle Target Labeling Assay, fragmented and hybridized according to Affymetrix's protocols.

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Protein sets define disease states and predict in vivo effects of drug treatment [heart]

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Protein sets define disease states and predict in vivo effects of drug treatment.

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