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CHRONIC POST-WEANING EXERICSE AND THE DEVELOPMENT OF OBESITY AND HYPOTHALAMIC PATHWAYS CONTROLLING ENERGY HOMEOSTASIS IN DIET-INDUCED OBESE RATS

by
Christa Patterson
Integrative Neuroscience Program

B.S. 2003, University of Pittsburgh


Thesis Advisor: Barry Levin, MD

Professor

Department: Neurology and Neurosciences

Cancer Center G 1196

Wednesday, August 6, 2008
10:00 a.m.


Abstract

Rodent models have become increasingly valuable in the study of the developmental aspects regulating obesity. The selectively-bred diet-induced (DIO) rat model of obesity is particularly informative because it shares several common characteristics with human obesity including polygenic inheritance, hyperleptinemia, insulin resistance, and hypertension. Similar to many humans, DIO rats become rapidly hyperphagic and obese when challenged with a moderate-fat, high-energy diet (HE). Prior to the development of obesity DIO rats have several neural abnormalities such as resistance to the anorectic effects of leptin and insulin compared to non-genetically predisposed animals. One explanation for this is that new neural circuits are formed during the developmental period that promote obesity. We have chosen to focus on this critical period of obesity development in juvenile DIO rats and assess the effect of voluntary wheel running on the formation of the neural circuits controlling food intake and body weight. Exercise has a selective effect on lowering adiposity in DIO vs. diet-resistant (DR) rats and despite their increased energy expenditure, these rats fail to compensate by increasing their caloric intake. Given these results, our central hypothesis was that exercise would positively alter the development of critical neural circuits regulating energy homeostasis in juvenile DIO rats to prevent the onset of obesity. We found that limited exposure to early-onset exercise has a sustained effect on preventing DIO rats from becoming obese, even after exercise cessation, despite continued intake of HE diet. Additionally, we found that post-weaning exercise was able to reverse the innate resistance of DIO rats to leptin on both a behavioral and molecular level, and that this effect persisted for several weeks beyond exercise termination. Furthermore, we have identified several exercise-induced peripheral factors which may prevent caloric compensation during exercise and may play a critical role in the ability of post-weaning exercise to permanently influence weight gain and adiposity in DIO rats. Elucidation of such factors and the mechanisms by which post-weaning exercise prevents obesity in DIO rats may be beneficial in the discovery of new pharmacological treatments for juvenile human obesity.


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