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Title: Defining the influence of peroxisome proliferator activated receptors on the metabolome of the mouse
Author: Atherton, Helen Jennifer
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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NMR spectroscopy and mass spectrometry based metabolomics has been used to investigate the function of PPARs in order to better define the role these receptors play in nutritional sensing, diabetes, obesity and the metabolic syndrome. Examining systemic metabolism in the PPAR-α null mouse and the interaction of phenotype with age, tissues from both fed and fasted mutant mice were characterised by a reduced concentration of glucose and impaired fatty acid oxidation (FAO). Both of these effects were most notable in the liver and increased with age. Additional changes in the PPAR-α null mouse were indicative of increased amino acid metabolism, impaired glucose metabolism regulation, myocardial damage, and substrate switching to maintain ATP homeostasis, the latter being particularly evident in muscle tissue. After a 24 hours fast, the PPAR-α null mouse demonstrated further abnormalities consistent with impaired ketogenesis, as well as increased lipogenesis and fatty acid accumulation in the liver and heart. PGC-1β is a transcriptional co-activator found primarily in highly oxidative tissues, and modulates the activity of many nuclear receptors, including PPAR-α and PPAR-γ. Surprisingly, the PGC-1β null mouse exhibited few signs of perturbed metabolism, except in the gastrocnemius where a perturbation in phosphocreatine concentration was observed in male mice aged 3 months. Finally, as deletion of nuclear hormone receptor (NHR)-49 in C. elegans causes disrupted lipid metabolism, a metabolomics functional genomic comparison was made between nhr-49and PPAR-α. The results demonstrate that nhr-49 has a similar role to mammalian PPAR-α with both receptors regulating pathways of lipid synthesis, FAO, glycolysis and gluconeogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available