Degree Name

Doctor Philosophy


School of Health Sciences, Faculty of Health and Behavioural Sciences


Obesity is a serious metabolic disorder that has reached epidemic proportions and has produced a heavy financial burden on health care systems worldwide. Obesity is usually induced by excessive energy intake and is highly resistant to treatment by lifestyle intervention. Using a mouse model, this study investigated the role of hypothalamic neuropeptides and neurotrophic factors in diet-induced obesity and obesity reversal by dietary interventions. Furthermore, this study tested the satiating capacity of various protein sources (whey, soy and gluten) through dietary intervention by analysing the meal pattern behaviour of mice. In the first two chapters, the mRNA expression of hypothalamic cocaine- and amphetamine- regulated transcript (CART), brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase B (TrkB) was examined by in situ hybridisation in dietinduced obese (DIO) and resistant (DR) mice following dietary intervention. CART mRNA expression was increased in the arcuate hypothalamic nucleus (Arc) and the paraventricular nucleus (PVN), and was decreased in the dorsomedial hypothalamic nucleus (DM) and lateral hypothalamic area (LH) of DIO mice compared to DR mice. These results demonstrated for the first time that two groups of CART neurons in the hypothalamus are differentially expressed in DIO mice. BDNF/TrkB mRNA expression was decreased in the hippocampus in DIO mice, suggesting a weakened inhibitory control of food intake. In the ventromedial hypothalamic nucleus (VMH), BDNF mRNA expression was lowered in DIO mice even after obesity reversal compared to DR mice. The low level of BDNF expression in the VMH may indicate an intrinsic nature of obese mice which makes them susceptible to overconsumption of a high-fat diet. Furthermore, energy restricted pair-feeding eliminated the differences between vii DIO and DR mice in both body weight and mRNA expression of hypothalamic CART and hippocampal BDNF/TrkB, which suggests that CART and BDNF/TrkB expression are related to body weight changes. The aim of the third chapter was to examine the expression of Arc orexigenic and anorexigenic neuropeptides in response to weight loss after chronic energy intake restriction. DIO and DR mice were placed on an energy restricted diet or continued on their high-fat diet ad libitum. An additional group was fed a low-fat diet throughout the entire study as controls. The results showed that chronic energy restriction corrected the obesity status and decreased plasma leptin in the DIO mice. Chronic energy restriction increased the expression of hypothalamic orexigenic neuropeptide Y (NPY) and agoutirelated protein (AgRP), however, it had no effect on the expression of Arc proopiomelanocortin (POMC) and CART mRNA. These results suggest that orexigenic NPY and AgRP (but not anorexigenic CART and POMC) may contribute to the reestablishment of a body weight set-point after body weight loss. Following on from the above three chapters which investigated the role of hypothalamic neuropeptides and neurotrophic factors in food intake, the fourth chapter investigated the satiating capacities of single or combined whey, soy and gluten protein diets through analysing the meal pattern behaviour of mice. It was found that the whey protein diet potently prolonged intermeal interval and diminished spontaneous meal frequency. This increase in intermeal interval, suggestive of postprandial and postabsorptive satiety effects, is mainly responsible for the inhibition of total energy intake after a whey protein diet. Combinations of whey and gluten caused a lower energy intake, longer inter-meal interval and lower meal number compared to the other paired combinations. Therefore, a combination of whey and gluten may be a better viii formula to provide a high satiety effect and suppress energy intake for antiobesity purposes. In conclusion, this thesis reveals that dietary intervention has a pronounced impact on the gene expression of hypothalamic neuropeptides and neurotrophic factors. High expression of orexigenic neuropeptides NPY/AgRP and low expression of BDNF/TrkB after weight loss may contribute to the recurrence of obesity. Combining dietary protein manipulations for maximising satiety with inhibition of the orexigenic neuropeptides and stimulation of BDNF/TrkB might be critical for potential treatment of obesity and maintenance of weight loss in human obese individuals.

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