Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Teresa M. Reyes

Abstract

Obesity is a costly and growing health concern for the modern world and puts individuals at increased risk for chronic illnesses. Although obesity is associated with many detrimental peripheral effects, food over consumption is centrally mediated. The hypothalamus and brainstem regions control homeostatic food intake, while hedonic food intake is mainly controlled by the central reward system. Palatable foods are rewarding and over ride the homeostatic system and cause over consumption. Foods high in sugar and fat acutely activate dopamine neurons in the classical reward pathway consisting of the ventral tegmental area projecting to the nucleus accumbens and prefrontal cortex. Chronic intake of palatable foods is associated with neuroadaptations that can lead to behavioral changes and further over consumption. This dissertation characterizes the behavioral, transcriptional, and circuitry changes in the central dopamine system after chronic high fat diet and high fat withdrawal in male and female mice. Four models of diet-induced obesity were examined. Chapters 2 and 3 examined diet induced obesity models and standard chow intervention in different age groups in order to reveal a developmental period sensitive to programming effects. We discovered that both age and sex were critical factors in the development and the reversal of neuroadaptations seen in obesity. Early life nutrition is particularly important to the developing brain and overnutrition during this time period leads to epigenetic changes that may contribute to the neuroadaptations that persist after intervention. In chapter 4, we examined exercise as an intervention to prevent the neuroadaptations and neuroinflammation associated with high fat diet intake. We discovered that although exercise had a beneficial effect of weight gain, it was not able to reverse reward dysfunction or neuroinflammation in all cases of high fat intake. It is possible that the neuroadaptations that occur after high fat consumption contribute to the difficulty individuals have with weight loss. Understanding how age and sex impact brain and behavior in the high fat withdrawal stage will have implication for obesity management and interventions. We know now that the brain of an individual is markedly different than the brain of a lean individual and these differences can predispose one to overconsumption during dietary intervention. Since both pharmacological and behavioral therapies are often combined with diet replacement, understanding the brain during this switch and factors that can raise adherence rates will help the success of therapies in the future.

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