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

描述(申请人提供)：减肥手术，特别是Roux-en-Y胃分流术(RYGB)，是目前唯一有效的治疗病态肥胖的方法，这是一个严重且日益严重的国家健康问题。RYGB增加饱腹感、减少进食和身体肥胖的机制还知之甚少。据认为，在进餐时过早吃饱和总摄入量减少的主要原因是Instera进入更远的小肠，即进入空肠，从而导致胃肠激素类高血糖素肽1(GLP-1)和酪氨酸酪氨酸(PYY)释放增加，导致肠道饱腹感增加。这一建议采用经典的大鼠模型，在肠道-大脑信号和脑神经处理的水平上测试RYGB对肠道饱足感的影响。RYGB将由一名在实验和临床上执行该技术的合作PIs进行，以确保实验模型和临床标准之间的紧密匹配。这些实验包括对假定受RYGB影响的摄取进行营养特定控制的测试。此外，还对内源性GLP-1和PYY的释放规律和饱和能力进行了测试。大脑工作建立在过去十年关于肠道负反馈控制进食的神经处理的进展的基础上，在尾部脑干和下丘脑。最后，由于美国患病态肥胖症的女性大约是男性的两倍，而且选择RYGB的患者中约85%是女性，所有拟议的实验都包括对生理性别差异、男女差异和女性雌激素调节效应的测试，后者与理解和治疗与更年期相关的肥胖症增加特别相关。我们提出了三个具体的目标：(1)确定RYGB手术是否增加空肠内输注Enure、Intralipid和葡萄糖的饱腹作用，包括脂肪组织丢失和性别差异的影响，即雌雄不同，雌二醇处理和未处理的卵巢切除大鼠；(2)确定RYGB手术对空肠内注入Seam、葡萄糖和Intralipid后脑内c-Fos表达的影响，并测定c-Fos表达的神经元的神经化学表型，包括性别差异(即雌雄不同，雌二醇处理与未治疗卵巢切除大鼠)的影响；(3)确定RYGB对空肠内注入Asure、Intralipid和葡萄糖的神经信号机制的影响，这些机制可能与空肠内注入SAURE、Intralipid和葡萄糖以及雌二醇处理与未治疗的卵巢切除大鼠相比。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)可以提出改进RYGB技术的策略，(3)应该为开发补充或取代RYGB的药物工具提供合理的基础，这对于不喜欢减肥手术或不建议进行减肥手术的患者尤其可取。 公共卫生相关性：减肥手术，特别是Roux-en-Y胃分流术(RYGB)，目前是治疗病态肥胖的唯一有效方法，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、减少进食和身体肥胖的机制还知之甚少。据认为，Instera进入更远端的小肠引起的肠道饱足感增加，导致胃肠激素GLP-1和PYY释放增加，是导致进餐早期饱腹感和总摄入量减少的主要原因。这一建议建立在经典的大鼠模型上，以测试RYGB在肠道-大脑信号和脑神经处理水平上对肠道饱足感的影响。此外，由于80%的RYGB患者是女性，该应用包括评估肠道饱腹症生理上的性别差异是否影响RYGB结果的实验。这项工作应该会带来新的见解，可能有助于改善减肥手术的进行方式，并可能为那些不希望或不适合减肥手术的患者提供替代减肥手术的药物靶点。

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. PUBLIC HEALTH RELEVANCE: 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 increased intestinal satiation caused by the entry of ingesta more distally into the small intestine, leading to increased release of the gut hormones GLP-1 and PYY, is the major cause of early satiation at meals and reduced overall intake. This proposal builds on classical rat models to test RYGB's effects on intestinal satiation, at the levels both of gut-brain signaling and of brain neural processing. In addition, as > 80% of RYGB patients are women, the application includes experiments to assess whether sex differences in the physiology of intestinal satiation affect RYGB outcome. This work should lead to new insights that may help improve how bariatric surgery is done and may suggest targets for pharmaceutical alternatives to bariatric surgery in patients for whom is it not desired or appropriate.