Degree Name

Doctor of Philosophy


University of Wollongong. Dept. of Biomedical Science


Obesity is a major predisposing factor for a variety of life threatening diseases such as Type II diabetes, hypertension and coronary heart diseases, resulting in enormous financial costs. Although recent research has demonstrated the importance of the central regulation of body energy balance, information on the development and maintenance of chronic cliet-induced obesity is still sparse. The aim of this thesis is to investigate the progressive course of development of chronic high fat diet-induced obesity. To achieve this goal, Experimental Section A was conducted to feed the mice with a high or low fat diet for up to 19 weeks to examine the progressive development of high fat diet induced obesity. This was then followed by the examinations of peripheral and central exogenous leptin sensitivity. In the Experimental Section B, the mRNA expressions of leptin receptor (LR), pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) in the hypothalamus were examined using quantitative in situ hybriclisation method. Furthermore, hypothalamic c-Fos-like immunoreactivity (FLI), alphamelanocyte- stimulating hormone (a-MSH), and NPY were also examined in this animal model.

In the Experimental Section A, the results demonstrated that long-term high fat feeding resulted in a progressive dysregulation of energy homeostasis. The process of development of high fat cliet-induced obesity (DIO) in C57 BIJ6J mice can be divided into three stages: 1) an early stage in response to high fat cliet that mice were sensitive to exogenous leptin; 2) a middle stage when mice had an increase in leptin production and still remained central leptin sensitivity; and 3) an increased food intake stage, accompanied by a reduction of centralleptin sensitivity.

The results from Experimental Section B showed a rise, then fall, of brain leptin receptor mRNA expressions, which corresponded to the Stages 2, and 3, of high fat dietinduced obesity defined in Experimental Section A. This rise, and associated decline in NPY mRNA levels, was associated with at least partially successful regulation of food intake, and if not adiposity, homeostasis. After a longer-term exposure to high fat feeding, a more profound breakdown occurred with overt hyperphagia and major obesity, associated with the reduced leptin receptor expression and failure of leptin stimulation of the POMe system. Furthermore, an increase in FLI activity in the lateral hypothalamus (LHA), dorsomedial hypothalamic nucleus (DMH), hypothalamic arcuate hypothalamic nucleus (Arc), and perifornical nucleus (PeF) of obese mice suggested that these areas might be involved in the central mechanisms of the high-fat diet induced obesity.

In conclusion, this study has provided new information for a better understanding of central factors controlling energy balance, and clarification of the central factors responsible for dysregulation of this system by chronic consumption of a high fat diet. The findings may also assist identification of therapeutic targets for treatment of chronic high fat diet-induced obesity.



Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.