Thesis (Ph. D.)--State University of New York at Binghamton, Dept. of Psychology, 2005. / Includes bibliographical references.

Thesis (Ph.D.) - University of St Andrews, May 2010.

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Thesis (Ph.D.)--Brown University, 2005. / Vita. Thesis advisor: Russell M. Church. Includes bibliographical references (leaves 101-107). Also available online.

Thesis (M.S.)--San Jose State University, 2005. / Includes abstract. Includes bibliographical references. ProQuest ; Subscription required for access to full text. Also available via the World Wide Web ;

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 192-211).

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 169-186).

Type 2 diabetes mellitus (T2DM) is mainly caused by genetic modifications and inappropriate life styles. The complexity of T2DM has brought us challenges for a comprehensive understanding of altered metabolic pathways that contributing to the development of T2DM. Therefore, a comprehensive metabolic analysis is needed. To date, taking regular exercise is a common and effective therapeutic way known to antagonize the metabolic disorders of T2DM. However, the regulatory effects of exercise on T2DM or T2DM induced complications have not been clearly characterized. Here, we present the effect of physical activity on biochemical changes in diabetic db/db mice in plasma, urine, skeletal muscle and kidney samples. Based on liquid chromatography coupled with high resolution Orbitrap mass spectrometry (LC-MS) and gas chromatography coupled with mass spectrometry (GC-MS), two major approaches, untargeted and targeted metabolomics studies, have been developed to delineate metabolic signatures in various kinds of biofluid and tissue samples. Targeted quantification methods on acylcarnitines and acyl-CoA have been developed. Untargeted metabolomics analysis by GC-MS and LC-MS have also been developed to draw a more comprehensive view of the metabolic changes in response to T2DM and exercise on db/db diabetic mice. The transcript expressions of mRNA in pathways of interest have also been measured to confirm the hypothesis. Firstly, a targeted quantification method of acylcarnitines by using high resolution parallel reaction monitoring (PRM) on LC-MS platform has been developed. A total of 117 acylcarnitines were detected from plasma and urine samples. The application of targeted profiling of acylcarnitines in db/m+ control and db/db diabetic mice indicated incomplete amino acid and fatty acid oxidation in diabetic mice. Interestingly, the reduction of medium odd-numbered chain acylcarnitines in urine samples was firstly observed between db/m+ and db/db mice. The high resolution PRM method makes it possible to monitor the widespread metabolic changes of the acylcarnitines in response to stimuli. Besides, the accurate MS and MS/MS spectra data of the 117 acylcarnitines could be used as mass spectrometric resources for the identification of acylcarnitines. In addition to targeted metabolomics analysis, untargeted metabolomics profiling analysis in plasma samples indicated that db/db diabetic mice may be more susceptible to exercise for energy expenditure. Interestingly, all the results from plasma, skeletal muscle and kidney samples may demonstrate that physical activity could mitigate insulin resistance in T2DM mice through improving fatty acid β-oxidation (FAO) and eliminating overloaded intermediate which contribute to insulin resistance. Specifically, the results from kidney samples demonstrated that exercise exhibit beneficial effect in reducing hyperlipidemia, expression levels of inflammatory markers (TNFα, IL-6 and COX2) and fibrosis markers (Collagen 1), and alleviating diabetic nephropathy (DN) induced mesangial expansion in kidneys of diabetic mice. The results of metabolic changes in kidney of db/db mice revealed that the accumulation of acyl-CoA, phospholipids and hydroxylated acylcarnitines were substantially ameliorated by exercise, and the reduction of important enzymes CTP1α and Acadl in FAO were partially reversed. In addition, branched-chain amino acids (BCAA) metabolism which positively related to inflammation (TNFα) was down-regulated in DN mice by exercise. What’s more, the accumulation of uric acid, which contributes to inflammation and tubulointestitial fibrosis in kidney disease, together with its six precursors have also been substantially reduced. The results in kidney samples demonstrated that in addition to beneficial effect in alleviating lipotoxicity through improving FAO efficiency, exercise also ameliorated diabetic induced inflammation and fibrosis via promoting BCAA catabolism and accelerating the elimination of uric acid. Together, the mass spectrometry-based metabolomics study is a powerful tool to investigate the regulatory effect of exercise on complex metabolic diseases. The results may provide informative insights into the underlying the mechanism of exercise on T2DM and T2DM induced complications.

Obesity and type II diabetes are associated with dementia and Alzheimer's disease. A high-fat diet induces memory deficits in rodents, however, complex episodic-like memory, has not been tested. Episodic memory is the recollection of events using a “what-where-when/which” experience and is the first memory to be compromised in Alzheimer's disease. To identify a link between a high-fat diet and episodic memory, 12 week old, male, C57Bl/6 mice, were fed a semi purified high-fat or low-fat diet ad libitum and tested with object-place-context (episodic-like), novel object recognition, object-place (spatial) and object-context (contextual) memory tasks for up to 2 weeks. A separate group of animals were fed a high-fat diet for 1 week followed by a low-fat diet for 1 week. Animals were killed after 3 days, 1 week or 2 weeks on diet. Brains were kept frozen until the hippocampus was dissected and proteomics performed. Further studies were carried out in rat primary hippocampal cell cultures to investigate the impact of different fatty acids on neuronal dendritic morphology. We found that episodic-like memory is compromised after only one day of a high fat diet together with spatial and contextual tasks. The ability to carry out the novel object recognition test remained intact. Proteomic analysis of hippocampal tissue revealed changes in a number of proteins associated with metabolism, cell stress, cell signalling, inflammation and the cytoskeleton. High-fat diet induced changes were reversed by a low-fat diet. Hippocampal neuron cultures showed that long chain saturated fatty acid palmitic acid, a component of the high-fat diet used in the behavioural and proteomic studies, caused reduced dendritic arborisation whist n-3 polyunsaturated fat docosahexaenoic acid negated these effects. These data link high-fat diet to indices of hippocampal neuronal damage and memory deficits and have implications for the link between diet, obesity and cognitive decline.