Pharmacogenomics of Gastric Function & Weight in Obesity

描述（由申请人提供）：控制食物摄入量，饭量和频率对肥胖的发展至关重要。胃对摄入的卡路里和体积发出饱腹的信号，因此在控制卡路里摄入方面发挥作用。我们的长期目标是开发基于药物的肥胖治疗方法，通过改变胃功能和饱腹感来限制食物摄入。血清素能和肾上腺素能的机制是本研究的重点，因为它们对饮食行为和肠道功能有影响。我们的中心假设是胃功能，由血清素能和肾上腺素能机制调节，改变食物摄入并影响肥胖的发展和治疗。基因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血清素再摄取抑制剂）治疗反应差异的关键。我们建议进行多学科调查，包括流行病学、行为学、生理学和药理学成分，以检验中心假设。在研究中，来自美国同一社区的肥胖参与者和年龄和性别匹配的对照组，我们将探索三个假设。假设1：肥胖与较低的餐后饱腹感和更大的胃肠道和心身症状负担有关。假设2：肥胖与上消化道生理异常有关，具体表现为空腹胃容量增加，餐后饱腹感和饱腹感降低。假设3和4：肥胖个体血清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（在目标3中评估）和体重减轻程度（在目标4中评估）的变化。我们将通过对社区正常体重（BMI 18.5 - 25kg/m2）、超重（BMI 25-29.9）和肥胖（bbb30）个体进行肠道和心身症状问卷调查，来描述饮食行为、胃肠道症状（包括饱腹感和饱腹感）。其次，我们将测量胃排空、空腹和餐后胃容量（使用经过验证的无创成像方法）、餐后饱腹感和饱腹感，以及餐后前8小时的综合血浆胃饥饿素、瘦素、胰岛素和肽YY水平。第三，我们将评估控制5 -羟色胺和肾上腺素能机制的候选基因对肥胖患者的生理反应和体重减轻的影响，10或15毫克西布曲明与安慰剂治疗12周。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型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.