DESCRIPTION (provided by applicant): Gastric bypass surgery (GBS) is an exceptionally successful therapy for morbid obesity and type 2 diabetes. GBS patients typically lose 25-35% of total body weight, demonstrate improvements in medical co- morbidities, and sustained weight loss over fifteen years. Given the epidemic of obesity in the United States, an improved understanding of the mechanisms by which GBS causes and maintains weight loss represents an important area of research. Although GBS mechanically restricts food intake, it also appears to reduce appetite and the appeal of savory meals. However, it is unclear why the motivational system fails to drive patients to compensate for this massive weight loss with increased food intake and preference for palatable, calorie-dense foods - the normal homeostatic response. Elucidating this paradox would substantially improve our understanding of the regulatory mechanisms for eating and body weight. We are in a unique position to address this question based on an animal model of GBS demonstrating alterations in the central neural mechanisms regulating food reward functions developed in our laboratory. The current study proposes behavioral, pharmacological, neurochemical and histological studies in high energy/high fat diet- induced obesity rat models to test the hypothesis that GBS alters appetite and food preference functions resulting in changes to the food reward system. The experiments target the nucleus accumbens, a critical structure for reward, with focus on two major transmitters: dopamine and acetylcholine. We propose four specific aims to test different components of this hypothesis. The first aim will establish the behavioral effects addressing specific aspects of food reward (i.e., incentive, reinforcement and hedonic value), and compare dopamine involvement in these behaviors across weight reduction methods (i.e. caloric restriction vs. GBS). The second and third aims will mechanistically address the underlying dynamic and static (i.e. neuroadaptive) signaling mechanisms, respectively. Aim 4 will investigate if increased gut-brain peptide signaling contributes to improved food reward functions following GBS. We believe the proposed research has significant potential to impact patient care as it will improve our understanding of factors that could positively or negatively contribute to long-term weight maintenance and could elucidate new targets for developing less invasive treatments for obesity. Preliminary data suggest GBS beneficially impacts the regulation of appetite and food choice resulting in more dramatic, sustained weight loss than dieting. The current study examines how GBS, in contrast to dieting, influences the rewarding effects of palatable food in the brains of dietary obese rats. Information concerning essential changes in motivated behavior and underlying neural substrates produced by GBS could assist in the development of effective non-surgical approaches to obesity treatment.
|Effective start/end date||4/1/09 → 3/31/14|