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Title: Metabolic consequences of obesity in the Zucker rat : a mass spectrometric and chemoinformatic study
Author: Leary, Laura Kate
ISNI:       0000 0004 7658 0566
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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The obesity epidemic has become one of the greatest healthcare challenges of recent times, and is a frequent co-morbidity of metabolic syndrome, a complex derangement of multiple metabolic pathological alterations mainly affecting energy metabolism, but which produces severe health impacts left untreated. In mammals, numerous homeostatic measures are exerted to counter excess caloric intake, but despite substantial investigation, the development, mechanisms and degrees of pathology in obesity are incompletely understood, particularly with respect to organ tissues. Organs are particularly vulnerable to pathological alterations caused by obesity, notably the heart, liver and pancreas. However, exploration of tissues in humans can be limited as biopsies are not without risk, and are not possible for certain organs, such as the pancreas. The obese Zucker rat is a well-characterised model of obesity and other aspects of metabolic syndrome (notably of insulin resistance and dyslipidemia). In this study, building on prior 1H-NMR spectroscopic investigation, comprehensive untargeted liquid chromatography-high resolution mass spectrometry was performed on aqueous and lipid whole tissue extracts from the heart, liver and pancreas tissue of both obese Zucker rats and lean control animals. Data were analysed using both univariate statistical approaches and multivariate techniques, and more than 250 metabolites were putatively identified in samples with either fragmentation data or retention time matching to authentic standards. Aqueous extracts of cardiac tissue did not indicate strong differences between lean and obese Zucker rats; however, lipid profiles differed substantially. Cardiac tissue in obese rats showed excess free fatty acids and acylcarnitine accumulation, suggesting cardiomyocyte β-oxidation could not keep pace with the nutrient influx. There was mild evidence of oxidative stress in obese rat heart, and of adaptive remodelling of heart tissue. Dyslipidemia was indicated in the livers of obese Zucker rats compared with lean controls, indicated by increased monounsaturated saturated fatty acids, loss of hepatic polyunsaturated fatty acids and triacylglycerol (TG) accumulation. Pancreatic tissue extracts showed consistent differences between phenotypes, reflecting clear differences in islet function despite the endocrine pancreatic tissue only forming a small proportion of pancreatic mass. Obese rats had increased pancreatic fatty acids, reduced arachidonic acid and creatine, changes in neurotransmittersrelated to pancreatic autocrine signalling, and alterations in phospholipids, all of which reflected increased insulin stimulation and phospholipase activity. Notably, metabolites associated with energy metabolism were generally only slightly altered between phenotypes in all tissues. TG species were nuanced and not systematically increased in obese rats, and overt TG accumulation was only observed in liver tissue, suggesting that the composition of TGs in plasma lipoproteins and tissues is not produced randomly. Reduced betaine, changes in phosphatidylcholines and phosphatidylethanolamines, and increased lysophospholipids were consistently observed in the tissues of obese rats, suggesting a systemic drain on these phospholipid species for export of lipoproteins by the liver, and remodelling of cellular lipid membranes, particularly in cardiomyocytes. These data suggest that despite their obvious dyslipidemia, and hypertrophy of the liver and heart, obese Zucker rats are able to adapt metabolically to the obese state, but these adaptations may render the organs of obese rats vulnerable to other pathological influences.
Supervisor: Nicholson, Jeremy ; Wilson, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral