Pharmacogenomics of Gastric Function & Weight in Obesity

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DESCRIPTION (provided by applicant): Control of food intake, size and frequency of meals are critical to the development of obesity. The stomach signals satiation in response to calories and volume ingested, and hence plays a role in control of calorie intake. Our long-term objective is to develop therapies for obesity based on pharmacological agents that will limit food intake by changes in gastric function and the sensation of satiation. The serotonergic and adrenergic mechanisms are the focus of this investigation because of their effects on eating behavior and gut functions. Our central hypothesis is that gastric functions, modulated by serotonergic and adrenergic mechanisms, modify food intake and impact on the development and treatment of obesity. Genetic variations are potentially key to inter-individual differences in responses to treatment with the appetite suppressant sibutramine, a norepinephrine and serotonin reuptake inhibitor. We propose a multi-disciplinary investigation with epidemiological, behavioral, physiological and pharmacogenetic components to test the central hypothesis. In studies drawing participants with obesity and age- and gender- matched controls from the same US community, we shall explore three hypotheses. Hypothesis 1: Obesity is associated with lower postprandial satiation, and greater gastrointestinal and psychosomatic symptom burden. Hypothesis 2: Obesity is associated with abnormal upper gastrointestinal physiology, specifically increased fasting gastric volume, and reduced postprandial satiation and satiety. Hypotheses 3 and 4: Genotypic differences in serotonergic and adrenergic mechanisms in obese individuals determine the change in fasting and postprandial gastric volumes (assessed in aim 3) and the degree of weight loss (assessed in aim 4) in response to 12 weeks' treatment with sibutramine. We shall characterize eating behaviors, gastrointestinal symptoms including satiation and satiety by validated bowel and psychosomatic symptom questionnaires in community samples of normal weight (BMI 18.5 to 25kg/m2), overweight (BMI 25-29.9), and obese (>30) individuals. Second, we shall measure gastric emptying, fasting and postprandial gastric volumes (using validated, non-invasive imaging methods), postprandial satiation and satiety, and integrated plasma ghrelin, leptin, insulin and peptide YY levels in the first8 postprandial hours. Third, we shall evaluate effects of candidate genes that control serotonergic and adrenergic mechanisms on physiological responses and weight loss to 12 weeks of treatment with 10 or 15 mg sibutramine vs placebo in obesity. In specific aim 4, we shall recruit African-American and Hispanic participants with the aid of local communities and their leaders. Our study will provide the first evidence for this novel therapeutic approach directed at changing intake through modulation of gastric functions. It will also identify physiological and genetic factors that predict therapeutic success in the treatment of obesity with sibutramine.