Neural mechanisms controlling food intake and body weight after bariatric surgery

描述（由申请人提供）：减肥手术已成为极端肥胖症的治疗选择，并且越来越多地被认为是治疗青少年甚至儿童肥胖症和非肥胖患者的糖尿病。在减肥和治疗糖尿病，高血压和睡眠障碍的成功率是非常高的，风险是最小的新腹腔镜手术。因此，减肥手术，特别是Roux-en-Y胃旁路手术（RYGB）是目前最有效的治疗肥胖症及其合并症。然而，关于所涉及的生理机制知之甚少。RYGB改变了能量平衡的许多方面，包括能量同化，分配和支出，但减少热量摄入和饮食行为的改变似乎是最重要的。我们建议使用大鼠模型来阐明RYGB手术后导致进食行为改变和食物摄入量和体重减少的激素和神经机制。我们的总体假设假设RYGB诱导的肠道信号变化影响了参与控制食物摄入和调节能量平衡的特定大脑系统，我们提出了三个目标来测试这一假设的具体方面。在第一个具体目标中，我们将确定尾侧脑干在RYGB诱导的食欲减退和体重减轻中的作用，因为大脑的这一部分通过迷走神经直接与肠道相连，并密切参与控制饱足感和进食量。在第二个具体目标中，我们将重点关注下丘脑回路，该回路有效地控制代谢需求驱动的食物摄入，并被认为负责长期的能量平衡。在第三个具体目标中，我们将评估皮质边缘系统的作用，这些系统被认为控制着进食的享乐、认知和情感方面。在每个目标中，我们将确定RYGB对特定行为和神经元激活模式的影响，并将其与循环激素水平的变化相关联。我们还将通过选择性中断外周和中枢的特定信号传导途径（包括迷走神经传入、PYY（3-36）、GLP-1和ghrelin），使用干预方法，以挽救RYGB后的异常进食表型。深入了解RYGB如何减少食物摄入量是重要的，原因有几个，即，外科手术的精细化、患者的行为管理以及模拟手术诱导效应的药物治疗的开发。 公共卫生相关性：胃旁路手术已被证明可以有效治疗严重肥胖症和治愈通常与肥胖相关的2型糖尿病。接受胃旁路手术的人报告说，他们不像以前那样饥饿，也不像以前那样一心想着食物。在这里，我们建议调查的生理机制，导致这些有益的变化，在大鼠模型的胃旁路手术的饮食行为。这将导致更优化的外科手术，帮助患者科普不同饮食习惯的行为提示，以及新药的开发。

DESCRIPTION (provided by applicant): Bariatric surgery has become the treatment of choice for extreme obesity and is increasingly also considered for the treatment of adolescent and even childhood obesity and diabetes in non-obese patients. The success rate in shedding body fat and curing diabetes, hypertension, and sleep disturbances is very high and the risk is minimal given the new laparoscopic procedures. Thus, bariatric surgery, particularly Roux-en-Y gastric bypass surgery (RYGB) is presently the most effective treatment of obesity and its comorbidities. And yet, little is known regarding the physiological mechanisms involved. RYGB changes many aspects of energy balance, including energy assimilation, partitioning, and expenditure, but decreased caloric intake and alterations in eating behavior appear to be the most important. We propose to use a rat model to elucidate the hormonal and neural mechanisms leading to altered eating behavior and decreased food intake and body weight after RYGB surgery. Our overarching hypothesis assumes that RYGB-induced changes in signals from the gut impinge on specific brain systems involved in the controls of food intake and regulation of energy balance, and we propose three aims to test specific aspects of this assumption. In the first Specific Aim, we will determine the role of the caudal brainstem in RYGB-induced hypophagia and weight loss, because this part of the brain is directly connected with the gut by the vagus nerve and intimately involved in the control of satiation and meal size. In the second Specific Aim, we will focus on the hypothalamic circuitry that potently controls metabolic need-driven food intake and is thought to be responsible for long-term energy balance. In the third Specific Aim, we will assess the role of cortico-limbic systems thought to control the hedonic, cognitive, and emotional aspects of eating. In each aim, we will identify effects of RYGB on specific behaviors and neuronal activation patterns, and correlate this with changes in circulating hormone levels. We will also use interventional approaches by selectively interrupting specific signaling pathways including vagal afferents, PYY(3-36), GLP-1, and ghrelin, in the periphery and centrally, in order to rescue the abnormal eating phenotype after RYGB. Insight into how RYGB decreases food intake is important for several reasons, i.e., refinement of the surgical procedure, behavioral management of patients, and development of pharmacological treatments that mimic the surgery-induced effects. PUBLIC HEALTH RELEVANCE: Gastric bypass surgery has been shown to effectively treat severe obesity and cure type-2 diabetes often associated with obesity. People with gastric bypass surgery report they are just not as hungry and preoccupied with thoughts about food as before. Here we propose to investigate the physiological mechanisms leading to these beneficial changes in eating behavior in a rat model of gastric bypass surgery. This will result in more optimal surgical procedures, behavioral tips helping patients to cope with different eating habits, and development of new drugs.