Neural mechanisms controlling food intake and body weight after bariatric surgery

描述(申请人提供)：减肥手术已经成为极端肥胖的治疗选择，也越来越多地被考虑用于治疗青少年甚至儿童肥胖症和非肥胖患者的糖尿病。在减掉体内脂肪和治愈糖尿病、高血压和睡眠障碍方面的成功率非常高，考虑到新的腹腔镜手术，风险很小。因此，减肥手术，特别是Roux-en-Y胃旁路手术(RYGB)是目前治疗肥胖症及其并发症最有效的方法。然而，人们对其中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、分配和消耗，但减少卡路里摄入量和改变饮食行为似乎是最重要的。我们建议使用一个大鼠模型来阐明导致RYGB手术后饮食行为改变、食物摄入量和体重减少的荷尔蒙和神经机制。我们的总体假设假设RYGB导致肠道信号的变化，影响到参与控制食物摄入和能量平衡调节的特定大脑系统，我们提出了三个目的来测试这一假设的特定方面。在第一个具体目标中，我们将确定尾侧脑干在RYGB引起的吞噬减少和体重减轻中的作用，因为大脑的这一部分通过迷走神经与肠道直接相连，并密切参与饱腹感和食物大小的控制。在第二个具体目标中，我们将重点放在下丘脑回路上，该回路有效地控制新陈代谢需求驱动的食物摄入，并被认为对长期能量平衡负责。在第三个具体目标中，我们将评估被认为控制饮食的享乐性、认知和情感方面的皮质-边缘系统的作用。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。我们还将使用干预方法，选择性地阻断特定的信号通路，包括迷走神经传入、PYY(3-36)、GLP-1和Ghrelin，在外周和中枢，以挽救RYGB后异常的进食表型。深入了解RYGB如何减少食物摄入量具有重要意义，原因有几个，即改进手术程序、患者的行为管理以及开发模拟手术诱导效果的药物治疗。 公共卫生相关性：胃旁路手术已被证明能有效治疗严重肥胖症和治愈经常与肥胖相关的2型糖尿病。接受胃旁路手术的人说，他们只是不像以前那样饿了，也不像以前那样全神贯注于食物的想法。在这里，我们建议在胃旁路手术的大鼠模型中研究导致这些有益的进食行为变化的生理机制。这将导致更优化的手术程序，帮助患者应对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.