Neural mechanisms controlling food intake and body weight after bariatric surgery

描述（由申请人提供）：减肥手术已成为治疗极度肥胖的首选，也越来越多地被考虑用于治疗青少年甚至儿童肥胖和非肥胖患者的糖尿病。在减少身体脂肪和治疗糖尿病、高血压和睡眠障碍方面的成功率非常高，而且由于有了新的腹腔镜手术，风险很小。因此，减肥手术，特别是Roux-en-Y胃旁路手术（RYGB）是目前治疗肥胖及其合并症最有效的方法。然而，人们对其中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，但减少热量摄入和改变饮食行为似乎是最重要的。我们建议使用大鼠模型来阐明RYGB手术后导致饮食行为改变、食物摄入量和体重减少的激素和神经机制。我们的总体假设是，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验证这一假设的具体方面。在第一个特定目标中，我们将确定尾侧脑干在rygb诱导的吞咽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，并密切参与饱腹感和食物大小的控制。在第二个特定目标中，我们将重点关注下丘脑回路，它有效地控制代谢需求驱动的食物摄入，并被认为是长期能量平衡的原因。在第三个特定目标中，我们将评估被认为控制饮食的享乐、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联系起来。我们还将采用介入性方法，选择性地阻断迷走神经传入、PYY（3-36）、GLP-1和ghrelin等外周和中枢的特定信号通路，以挽救RYGB后异常进食表型。了解RYGB如何减少食物摄入是很重要的，有几个原因，即手术过程的改进，患者的行为管理，以及模仿手术引起的影响的药物治疗的发展。

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.