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• W2756157788 abstract "Human obesity is a world-wide health crisis thatpromotes insulin resistance and type 2 diabetes. Obesity increasesintracellular free fatty acid concentrations in peripheral tissues,particularly the liver, which disrupts molecular mechanisms thatmaintain normal glycemia in response to fasting and feeding. Theprogression towards outright pathology in response to obesity is ahighly complex process that involves coordinated dysregulation of avariety of molecular processes across multiple regulatory levels.The goal of this thesis was to apply a quantitative, multi-omicsystems biology approach to the study of obesity-induce hepaticinsulin resistance. We fed male C57BL/6J mice high-fat diets (HFD)to induce obesity and insulin resistance. In the first presentedstudy, our group collected datasets to profile the hepaticepigenomes, transcriptomes, proteomes, and metabolomes of chow diet(CD) control and HFD-fed mice. I extended and applied anestablished computational modeling algorithm, namely theprize-collecting Steiner forest (PCSF), to simultaneously integratethese molecular data with protein-protein and protein-metaboliteinteractions into a tractable network model of hepaticdysregulation. This model uncovered a variety of dysregulatedpathways and processes, some of which are not well-establishedaspects of insulin resistance. We further tested and validated someof these model predictions, finding that HFD induces seriousarchitectural defects in the liver and enhances hepatocyteapoptosis. In the next study, we focused more specifically onhepatic transcription. We fed mice short and long-term HFDs andtreated them with the type 2 diabetes drug metformin. Compared tonon-treated CD controls, diet exerted the strongest effect ontranscription, progressively inducing changes as HFD durationincreased. We additionally stimulated mice with insulin andcollected temporal transcriptomic profiles. We found that long-termHFD almost completely blunted normal insulin-inducedtranscriptional changes, but also found a small set of genes thatare specifically insulin-responsive in HFD livers. We furthercharacterized one of these genes and provided evidence supportingthe notion that aspects of hepatic insulin signaling are intactduring insulin resistance. In another study, we collectedtranscriptomic and epigenomic data from mice fed acalorie-restricted (CR) diet. Interestingly, we found a small setof genes altered in the same direction by both CR and HFD. We thenused chromatin accessibility experiments to infer regulatorsassociated with these gene expression changes and found roles forPPAR[alpha] and RXR[alpha]. We performed ChIP-Seq experiments forthese factors and treated mice and primary hepatocytes with aPPAR[alpha] activator, uncovering a role for PPARα in theregulation of anaerobic glycolysis. We also validated novelpredicted target genes of PPAR[alpha] involved in glucosemetabolism. Finally, we profiled hepatic miRNAs in CD and HFDlivers, finding that HFD progressively alters their expression…" @default.
• W2756157788 created "2017-09-25" @default.
• W2756157788 creator A5066829487 @default.
• W2756157788 date "2017-01-01" @default.
• W2756157788 modified "2023-09-23" @default.
• W2756157788 title "Systems biology of diet-induced hepatic insulin resistance" @default.
• W2756157788 hasPublicationYear "2017" @default.
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