Doctor of Philosophy
School of Health Sciences
South, Timothy, The role of palatable feeding-related receptors in macronutrient preference and diet-induced obesity in mice, Doctor of Philosophy thesis, School of Health Sciences, University of Wollongong, 2008. http://ro.uow.edu.au/theses/1995
Obesity is a serious metabolic disorder that is reaching epidemic proportions worldwide. One likely reason for this is an increase in energy intake by certain individuals. This project aimed to examine the role of palatable feeding-related receptors in the regulation of energy intake, macronutrient preference and obesity development. This was achieved through an integrative approach that used dietary intervention, pharmacological manipulation, blood hormone analysis and receptor binding assays.
The first study of this project aimed to develop a dietary fat-preferring obese-prone mouse model. The macronutrient preference of five mouse strains (AKR, A/J, ARC, C57Bl/6 and BALB/c) was examined by placing them on a two-choice high fat and low fat diet protocol for thirty days. It was found that the C57Bl/6 strain was not only the strongest fat preferrer consuming 72% of their calories from the high-fat diet, but also the most obesogenic of the inbred strains.
The next study aimed to determine if drugs that act on palatable feeding-related receptors can alter the energy intake and macronutrient preference of the fat-preferring C57Bl/6 mice. Intraperitoneal injection with the CB1 inverse agonist AM 251, the opioid mu antagonist β-Funaltrexamine and the D2 receptor agonist Bromocriptine similarly reduced total energy intake a specific reduction of high fat diet intake with no change in low fat diet intake.
The third and final study in this project aimed to examine how the expressions of the CB1, D2 and opioid mu receptors are altered in the early and late stages of high fat diet induced obesity. A ligand binding assay was performed on the cannabinoid CB1 receptor, opioid mu receptor, dopamine D2 receptor and dopamine transporter (DAT) of C57Bl/6 mice that were fed a high fat diet for three and twenty weeks. It was found that central CB1 and D2 receptor binding was increased in reward and feeding-related brain areas following three weeks of high fat feeding and the CB1 receptor was decreased following twenty weeks of high fat feeding. Three and twenty weeks of high fat feeding was found to have no effect on opioid mu receptor binding levels. In contrast, replacement of the high fat diet at three weeks with a low fat diet for one and seven days caused an increase in opioid mu receptor binding in the nucleus accumbens and amygdala but had no effect on CB1, D2 and DAT binding levels. This raises the possibility that unlike the CB1 receptor, D2 receptor and DAT, the opioid mu receptor is influenced by alterations in short term energy intake and macronutrient type rather than long term changes in obesity level. Conversely, the temporal changes in CB1 and D2 receptor binding that occurred throughout the development of diet-induced obesity may indicate the important role of these systems in the pathology of this disease.
In conclusion, this study has provided new information regarding the involvement of palatable feeding-related receptors in macronutrient preference and obesity development in mice. These findings may assist not only in understanding the aetiology of obesity but may aid in the design of new pharmacological treatments for this disease.