Energy balance and cancer risk : metabolic and molecular studies

Over 60% of U.S. adults are either overweight or obese. The effect of obesity on cancer mortality is striking: approximately 90,000 deaths per year from cancer may be avoided if Americans could maintain a BMI of <25.0 throughout adulthood. The aim of this research was to employ and evaluate energy balance interventions designed to reverse obesity-related risk factors. The overarching hypothesis was that energy balance interventions would reduce cancer risk. To test this hypothesis, we used mostly animal models of diet-induced obesity and tested the effect of a low carbohydrate diet, calorie restriction, and exercise on adiposity, levels of circulating hormones, insulin resistance, and oxidative stress. To extend on in vivo findings from the final animal study, we utilized a human breast cancer cell line to further characterize the gene expression of thioredoxin-interacting protein in the context of p53 deficiency. Calorie restriction was the most potent energy balance intervention. It caused weight loss, slowed tumor growth, reduced circulating IGF-1 and leptin levels, improved insulin resistance, and elicited a robust transcriptional response in visceral white adipose tissue following weight loss. Although a low carbohydrate diet and exercise did decrease hormones associated with obesity, (IGF-1 and leptin respectively) calorie restriction proved to be the most effective at reducing multiple obesity-related factors. Finally, from our studies analyzing the effect of obesity and exercise on oxidative stress in the context of p53-deficiency, we discovered that thioredoxin-interacting protein is transcriptionally upregulated in response to increased glucose flux associated with metabolic dysregulation that occurs as a consequence of loss of p53.