Intestinal satiation in Roux-en-Y gastric bypass rats: brain mechanisms and sex d

描述（由申请人提供）：减肥手术，特别是Roux-en-Y胃旁路术（RYGB）手术，是目前治疗病态肥胖的唯一有效疗法，病态肥胖是一个严重且日益严重的国家健康问题。RYGB增加饱腹感和减少进食和身体肥胖的机制知之甚少。人们认为，进食时过早饱腹和总摄入量减少的主要原因是摄入物更远端进入小肠引起的肠道饱腹感增加，即，进入空肠，从而导致肠激素胰高血糖素样肽1（GLP-1）和肽酪氨酸酪氨酸（PYY）的释放增加。本研究采用经典的大鼠模型，从肠-脑信号和脑神经加工两个层面来检测RYGB对肠道饱足的影响。RYGB将由一名在实验和临床上执行该技术的共同PI完成，以确保实验模型和临床标准之间的密切匹配。这些实验包括对假设受RYGB影响的特定营养素摄入控制的测试。此外，测试了内源性GLP-1和PYY的释放模式和饱足效力。大脑的工作建立在过去十年的进展，涉及神经处理的肠道负反馈控制吃在尾脑干和下丘脑。最后，因为在美国患有病态肥胖的女性是男性的两倍，并且因为选择RYGB的患者中约85%是女性，所以所有拟议的实验都包括生理性别差异的测试，男女差异和女性雌激素调节效应，后者特别与理解和治疗与更年期相关的肥胖增加有关。提出了三个具体目的：（1）确定RYGB手术是否增加了空肠内输注Ensure、Intramidoid和葡萄糖的饱腹作用，包括脂肪组织损失和性别差异的影响，即，雄性与雌性和雌二醇处理与未处理的卵巢切除大鼠;（2）确定RYGB手术对脑c-Fos表达的影响，以响应Ensure、葡萄糖和Intradheroid的空肠内输注，并确定表达c-Fos的神经元的神经化学表型，包括性别差异的影响，即，雄性与雌性以及雌二醇处理的与未处理的卵巢切除大鼠，以及（3）确定RYGB对神经信号传导机制的影响，所述神经信号传导机制是雄性与雌性以及雌二醇处理的与未处理的卵巢切除大鼠空肠内输注Ensure、Intradolid和葡萄糖的饱腹作用的基础。使用了最先进的行为、生理和分子技术。因此，这项工作（1）应该有助于为RYGB患者提供行为和营养咨询，（2）可以建议改善RYGB技术的策略，以及（3）应该为开发药物工具以增加或取代RYGB提供合理的基础，这对于不希望进行减肥手术或不推荐进行减肥手术的患者尤其有利。

DESCRIPTION (provided by applicant): Bariatric surgery, in particular Roux-en-Y gastric bypass (RYGB) surgery, is currently the only effective therapy for morbid obesity, which is a grave and growing national health problem. The mechanisms through which RYGB increases satiation and reduces eating and body adiposity are poorly understood. It is thought that the major cause of early satiation at meals and reduced overall intake is increased intestinal satiation caused by the entry of ingesta more distally into the small intestine, i.e., into the jejunum, thus leading to increased release of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY). This proposal adapts classical rat models to test RYGB's effects on intestinal satiation, at the levels of both of gut-brain signaling and of brain neural processing. RYGB will be done by one of the co-PIs who performs the technique both experimentally and clinically, assuring a close match between the experimental model and the clinical standard. The experiments include tests of nutrient-specific controls of ingestion that are hypothesized to be affected by RYGB. In addition, both the release patterns and the satiating potency of endogenous GLP-1 and PYY are tested. The brain work builds on progress in the past decade concerning the neural processing of intestinal negative-feedback controls of eating in the caudal brainstem and in the hypothalamus. Finally, because about twice as many women than men suffer from morbid obesity in the USA and because about 85% of patients electing RYGB are women, all the proposed experiments include tests of physiological sex differences, both male-female difference and estrogen-regulated effects in females, the latter especially relevant to understanding and treating the increase in adiposity associated with menopause. Three Specific Aims are proposed: (1) Determine whether the satiating actions of intra-jejunal infusions of Ensure, Intralipid and glucose are increased by RYGB surgery, including the impacts of adipose-tissue loss and of sex differences, i.e., male vs. female and estradiol-treated vs. untreated ovariectomized rats; (2) Determine the effects of RYGB surgery on brain c-Fos expression in response to intra-jejunal infusions of Ensure, glucose and Intralipid, and determine the neurochemical phenotypes of neurons expressing c-Fos, including the impact of sex differences, i.e., male vs. female and estradiol-treated vs. untreated ovariectomized rats and (3) Determine the effects of RYGB on neural signaling mechanisms underlying the satiating actions of intra-jejunal infusions of Ensure, Intralipid and glucose in male vs. female and in estradiol-treated vs. untreated ovariectomized rats. State-of-the-art behavioral, physiological and molecular techniques are used. Thus, the work (1) should help inform behavioral and nutritional counseling for RYGB patients, (2) may suggest strategies for improvement in the RYGB technique, and (3) should provide rational bases for the development pharmaceutical tools to augment or replace RYGB, which is especially desirable for patients who do not desire bariatric surgery or for whom it is not recommended.