Pharmacogenomics of Gastric Function & Weight in Obesity

描述（由申请人提供）：控制食物摄入量、进食量和频率对肥胖的发展至关重要。胃响应于摄入的卡路里和体积发出饱足信号，因此在控制卡路里摄入方面起作用。我们的长期目标是开发基于药理学药物的肥胖治疗方法，通过改变胃功能和饱足感来限制食物摄入。由于其对进食行为和肠道功能的影响，故肾上腺素能和肾上腺素能机制是本研究的重点。我们的中心假设是，胃功能，调节肾上腺素能和肾上腺素能机制，修改食物摄入量和影响的发展和治疗肥胖。遗传变异可能是个体间对食欲抑制剂西布曲明（一种去甲肾上腺素和5-羟色胺再摄取抑制剂）治疗反应差异的关键。我们提出了一个多学科的调查与流行病学，行为，生理和药物遗传学的组成部分，以测试中心的假设。在研究中，我们将从同一个美国社区中抽取肥胖症患者和年龄和性别匹配的对照组，探讨三个假设。假设1：肥胖与较低的餐后饱足感，以及更大的胃肠道和心身症状负担有关。假设二：肥胖与上消化道生理异常有关，特别是空腹胃容量增加，餐后饱腹感和饱腹感减少。假设3和4：肥胖个体中β-肾上腺素能和肾上腺素能机制的基因型差异决定了西布曲明治疗12周后空腹和餐后胃容量的变化（在目的3中评估）和体重减轻程度（在目的4中评估）。我们将在正常体重（BMI 18.5 - 25 kg/m2）、超重（BMI 25-29.9）和肥胖（>30）个体的社区样本中，通过经验证的肠道和心身症状问卷来描述饮食行为、胃肠道症状（包括饱食和饱腹感）。其次，我们将测量胃排空、空腹和餐后胃容量（使用经验证的非侵入性成像方法）、餐后饱腹感和饱腹感，以及餐后前8小时内的综合血浆ghrelin、瘦素、胰岛素和肽YY水平。第三，我们将评估候选基因的影响，控制肾上腺素能和肾上腺素能机制的生理反应和体重减轻12周的治疗与10或15毫克西布曲明与安慰剂的肥胖。在具体目标4中，我们将在当地社区及其领导人的帮助下招募非洲裔美国人和西班牙裔参与者。我们的研究将为这种通过调节胃功能来改变摄入量的新治疗方法提供第一个证据。它还将确定预测西布曲明治疗肥胖成功的生理和遗传因素。

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.