Exercise-induced hypothlamic structure & function: implications for energy balance & obesity

Obesity has reached epidemic proportions worldwide, and for the first time in human history more people in the world are overweight than undernourished. Understanding the route of metabolic dysfunction during obesity remains a major medical challenge. The hypothalamus is integral to the control of food intake and becomes dysfunctional during obesity. This is a key event in the pathogenesis of obesity. This thesis sort to identify possible routes of hypothalamic dysfunction during obesity, and to investigate the potential benefits of regular exercise training on hypothalamic function. This thesis found that lipid accumulation occurs in the hypothalamus of mice fed a high fat diet. Specifically, diacylglycerol and ceramide content are increased, and these lipids are known to interfere with insulin signalling in peripheral tissues such as skeletal muscle and liver. Six weeks of exercise training was unable to decrease lipids in the hypothalamus, despite improving body weight and whole body glucose metabolism. Neurogenesis in the hypothalamus has been proposed to play a role in the regulation of food intake and body weight. This thesis showed that a single exercise bouts upregulates genes in the hypothalamus that promote neurogenesis and stem cell activation; while just 7 days of exercise training was able to stimulate neurogenesis in the hypothalamus of both lean and obese mice. By using the mitotic blocker, cytosine-~-D-arabinofuranoside, to block neurogenesis it was found that neurogenesis during four weeks of exercise may play a role in insulin-stimulated metabolism in the adipose tissue of high fat fed mice. Furthermore, when hypothalamic neurogenesis was stimulated with the cytokine CNTF, which results in a I 7- fold greater amount of neurogenesis than exercised mice, there were no sustained effects on body weight or peripheral insulin action. Therefore, while exercise training stimulates hypothalamic neurogenesis, its role in body weight and energy balance is yet to be fully elucidated. Finally, this thesis examined the effect of six weeks of exercise training on hypothalamic sensitivity to peripheral hormones, which is impaired during obesity. Contrary to previously published work showing increased hypothalamic sensitivity to leptin directly after exercise in both lean and obese mice; this thesis showed that exercise training does not confer long term changes to hypothalamic sensitivity to leptin or ghrelin. Collectively, this thesis highlights that while exercise training during obesity is able to alter the structure of the hypothalamus through the induction of neurogenesis, functional outcomes remain largely unaltered.