Unknown,Transcriptomics,Genomics,Proteomics

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Genetic Variation Determines PPARγ Function and Antidiabetic Drug Response In Vivo [ChIP-seq]

ABSTRACT: SNPs affecting disease risk often reside in non-coding genomic regions. Here we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof-of- concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome- wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response. 6 ChIP-seq experiments conducted in mice and 5 in human subjects. Deep sequencing carried out using Illumina HiSeq2000 and the Solexa Analysis Pipeline eWAT; epididymal White Adipose Tissue iWAT; inguinal White Adipose Tissue 12wLFD; mice were fed a control low fat diet (Research Diet D12450B) chow; mice were fed standard rodent chow Diet GR; Glucocorticoid receptor

ORGANISM(S): Homo sapiens

SUBMITTER: Mitchell Lazar

PROVIDER: E-GEOD-64458 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:SNPs affecting disease risk often reside in non-coding genomic regions. Here we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof-of- concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome- wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response. Comparison of 5 RNA-seq experiments between 2 strains of mice differing in diet and fat depot. One of the experiments was evaluation of the response to a drug Rosiglitazone. Our RNA-seq data comprises primarily of 4 main experiments: The first experiment consists of samples taken from 2 strains of mice and their F1 progeny The samples are all taken from the same depot and when the mice were fed the same chow diet The second experiment has 2 parts, the first one involves samples taken from the 2 strains from the same eWAT depot when they were kept on a Low Fat Diet (LFD) This first part serves as a control for the second one in which the mice were treated with a drug, rosiglitazone in conjunction with a LFD The third experiment consists of samples taken from mice being fed on LFD. The samples are taken from the eWAT depot for both the strains. The fourth experiment consists of samples taken from mice being fed on LFD. The samples are taken from the iWAT depot for both the strains. We also have a solitary sample from a GRO-seq experiment which was done on eWAT in a B6 strain of mice being fed a LFD eWAT: epididymal White Adipose Tissue iWAT: inguinal White Adipose Tissue LFD-12w: mice were fed a control low fat diet (Research Diet D12450B) chow: mice were fed standard rodent chow Diet LFD w/rosiglitazone: Drug rosiglitazone (Cayman Chemicals) was incorporated into low fat diet D12450B by Research Diets at 36mg/kg of diet. Mice received control low fat diet for 10 weeks (age 6-16 weeks), and the rosiglitazone-containing diet versus control diet for the final 2 weeks (until sacrifice at 18 weeks) LFD control for rosi: mice were fed a control low fat diet (Research Diet D12450B)

Project description:Increased visceral adiposity and hyperglycemia, two characteristics of metabolic syndrome, are also present in conditions of excess glucocorticoids (GCs). GCs are hormones thought to act primarily via the glucocorticoid receptor (GR). GCs are commonly prescribed for inflammatory disorders, yet their use is limited due to many adverse metabolic side effects. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies as to the exact role of MR in metabolic disease. Using MR knockout mice (MRKO), we find that both white and brown adipose depots form normally when compared to wild-type mice at P5. We created mice with adipocyte-specific deletion of MR (FMRKO) to better understand the role of MR in metabolic dysfunction. Treatment of mice with excess GCs for 4 weeks, via corticosterone in drinking water, induced increased fat mass and glucose intolerance to similar levels in FMRKO and floxed-control mice. Separately, when fed a high-fat diet for 16 weeks, FMRKO mice had reduced body weight, fat mass, and hepatic steatosis, relative to floxed-control mice. Decreased adiposity likely resulted from increased energy expenditure since food intake was not different. RNA sequencing analysis revealed decreased enrichment of genes associated with adipogenesis in inguinal white adipose of FMRKO mice. Differentiation of mouse embryonic fibroblasts (MEFs), showed modestly impaired adipogenesis in MRKO MEFs compared to wild-type, but this was rescued upon the addition of peroxisome proliferator-activated receptor gamma (PPARγ) agonist or PPARγ overexpression. Collectively, these studies provide further evidence supporting the potential value of MR as a therapeutic target for conditions associated with metabolic syndrome. Method (Chow): At six weeks of age mice were maintained on a chow diet (PicoLab® Rodent Diet 20 5053* [20% protein]) for 16 weeks Method (High Fat Diet): 6 week-old mice were fed ab libitum with Teklad TD.88137 (21.2% fat [42% kcal fat], 48.5% carbohydrate [34% sucrose by weight], 17.3% protein, and 0.2% cholesterol by weight) for 16 weeks Method (Corticosterone): 10-11-week-old mice were administered corticosterone via drinking water (100 μg/mL) for 4 weeks, while maintained on a chow diet

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Genetic Variation Determines PPARγ Function and Antidiabetic Drug Response In Vivo [ChIP-seq]

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