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Abstract
With the increasing incidence of obesity and related diseases there is a great deal of interest in understanding the impact of a western diet on long term health. Moreover, diet and aging are linked to insulin resistance a major risk factor for a constellation of diseases including osteoporosis, Alzheimer’s disease and type 2 diabetes. However, the direct contribution of diet versus aging to these processes is not clear. Our investigation begins in chapter 3 where we establish and characterise a model of high-fat diet-induced obesity in the form of the HFD fed C57BL/6 mouse. Using the established model we then validate the therapeutic potential of VEGF neutralisation on insulin resistance, and discovered that αVEGF therapy was able to reverse whole body glucose intolerance, via an improvement in hepatic insulin sensitivity. Using the knowledge developed in Chapters 3 and 4 we then returned to our original question and designed a study, which could address two aspects: 1) Track the acute and long term metabolic consequences and/or adaptations to a HFD, and 2) quantify the relative contribution of diet and age to disease, beyond glucose metabolism. HFD feeding resulted in significant glucose intolerance within 1 d of feeding and this was sustained for 6 months after which it began to resolve until complete resolution by 12 months on the diet. The resolution of glucose intolerance was due to a striking compensation by the pancreas as a result of beta cell proliferation. Preliminary studies indicate that this may be due to an unexpected stimulatory effect of leptin on insulin secretion. The HFD also caused marked deterioration in bone morphology and brain function, as measured by memory deficit and a change in the Amyloid Beta 40 to 42 ratio. The effect of aging per se on each of these parameters was mild compared to the effect of diet. We conclude that western style diets have profound deleterious effects on multiple organ systems and the effect of diet is much more potent than age alone.