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Title: The effect of obesity on diurnal variation in cardiovascular and metabolic processes in a mouse model of diet-induced obesity
Author: Prasai, Madhu Janina
ISNI:       0000 0004 2748 0462
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Physiological processes display intrinsic circadian variations which are controlled by an endogenous circadian timing mechanism. Metabolic disease comprising type 2 diabetes and obesity is a recognised risk factor for cardiovascular disease (CVD). The early phase of atherosclerotic CVD is endothelial dysfunction and, like pre- diabetic insulin resistance, is a major focus of study. Metabolic and vascular disease may be linked through insulin resistance, which is now recognised to be a critical risk factor for the development both of endothelial dysfunction and of type 2 diabetes. A circadian component to cardiovascular and metabolic disease is evident from observations of human populations and recently critical animal studies have begun to elucidate the underlying mechanism. It is not known if circadian dysfunction is a central feature of acquired cardiometabolic disease, or if so at which stage in the disease process it develops. The effect of acquired insulin resistance upon circadian variation in insulin sensitivity and insulin signalling is also unclear. In a mouse model of diet-induced obesity, it was hypothesised that obesity is associated with pathological diminution of diurnal rhythms of systemic and cellular homeostasis and that such diminution is particularly associated with the occurrence of insulin resistance. In the cardiovascular system, aortic endothelial vasomotion studies and qPCR showed no loss of rhythm in obese animals despite clear differences in endothelial phenotype between obese and lean. When the focus of investigation was shifted to other insulin-sensitive tissues, the predicted attenuation of rhythm was found, with widespread diurnal abnormalities in obesity of systemic insulin and glucose homeostasis, rhythmic transcription of clock genes and downstream clock-controlled genes important to metabolic homeostasis, including AMPK. A gradient of tissue sensitivity to circadian disruption was seen, with marked disruption in visceral adipose but fully preserved rhythms in liver and aorta. Patterns of circadian disruption closely mirrored those of tissue inflammation but did not correspond to impaired insulin signalling, which was most marked in liver, followed by aorta. These findings put circadian disruption into the context of tissue- specific events in obesity. They suggest that circadian disruption and insulin resistance arise by distinct processes and prompt speculation regarding the cellular mechanism by which circadian disruption may arise in obesity. 3
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available