The Role of Adipose Tissue Remodeling in Surgically-Induced Weight Loss

描述(由申请人提供)：肥胖及其相关的并发症，如2型糖尿病，给患者、社会和经济带来了巨大的负担。到目前为止，能够有效地诱导持续减肥的药物干预措施的发展一直受到阻碍，主要是因为缺乏对导致肥胖的确切路径生理机制的了解。因此，减肥手术，特别是Roux-en-Y胃分流术(RYGB)，仍然是病态肥胖患者唯一有效的治疗方法。RYGB显著改变了体重和能量平衡。因此，它代表了一种独特的实验模型，用于科学研究代谢放松和肥胖的潜在机制。脂肪组织在能量消耗的调节中起着核心作用，其功能障碍已被证明会导致肥胖。在这个应用中，我们建议研究RYGB对脂肪组织功能、表型和代谢率的影响。这项建议要检验的中心假设是，RYGB的深刻生理效应部分是通过诱导和激活白色和棕色脂肪组织(分别为WAT和BAT)中的棕色脂肪来调节的。这项应用的总体目标是确定WAT和BAT在多大程度上促进了RYGB后代谢率的增加，并最终减轻了体重。具体目标1是 评估RYGB治疗后每种脂肪类型的代谢和表型重构的程度。首先，将在手术后三个月内确定几个WAT和BAT仓库中棕色脂肪患者数量的变化。将采用基因组、蛋白质组和形态计量技术。其次，RYGB诱导的脂肪组织代谢率的变化将通过测量体外组织培养中的呼吸速率来阐明。具体目标2也由两个子目标组成。首先，将确定Wat Proceding RYGB中出现的棕色脂肪细胞的来源。方法是用BrdU标记增殖的脂肪前期，并确定标记是否扩散到新的棕色脂肪细胞。其次，将通过全基因组表达来确定参与WAT和BAT重塑的关键基因和分子途径。最后，在具体目标3中，将确定棕色脂肪在手术后能量平衡调节中的作用。为此，将使用UCP1基因敲除小鼠，并将评估RYGB诱导的体内代谢率、WAT和BAT表型以及WAT和BAT特定能量消耗的变化，并将其与野生型小鼠进行比较。关于预期结果，我们预计，通过诱导和激活棕色脂肪，RYGB在WAT和BAT中诱导了戏剧性的表型和代谢变化。这些改变与手术后能量消耗的增加有关，阻碍棕色肥胖的诱导显着削弱了手术的治疗效果。 公共卫生相关性：美国人口健康的未来取决于确定和提供有效的肥胖症治疗策略。这项建议旨在阐明脂肪组织在RYGB后调节代谢率和体重中的作用以及涉及的分子途径。这一结果将为减肥药物的开发提供新的靶点。

DESCRIPTION (provided by applicant): Obesity and its associated comorbidies such as type 2 diabetes mellitus, impose a significant burden on patients, society, and the economy. So far development of pharmacological interventions that can effectively induce sustained weight loss has been hindered, mainly by the lack of knowledge about the precise path physiological mechanisms leading to obesity. As a result, weight loss operations, particularly Roux-en-Y gastric bypass (RYGB) surgery, remain the only definitive treatment available to morbidly obese patients. RYGB significantly alters body weight and energy balance. Therefore, it represents a unique experimental model for the scientific investigations on the underlying mechanisms involved in metabolic deregulation and obesity. Adipose tissue plays a central role in the regulation of energy expenditure and its dysfunction has been shown to lead to obesity. In this application, we propose to study the effects of RYGB on adipose tissue function, phenotype, and metabolic rate. The central hypothesis to be tested in this proposal is that the profound physiological effects of RYGB are partially mediated by induction and activation of brown adiposities within both white and brown adipose tissues (WAT and BAT, respectively). The overall objective of this application is to determine the degree to which WAT and BAT contribute to the increase in metabolic rate, and ultimately weight loss, after RYGB. The specific aim 1 is to assess the extent of the metabolic and phenotypic remodeling of each fat type after RYGB. First, the changes in the population of brown adiposities in several WAT and BAT depots will be determined over a period of three months after surgery. Genomic, proteomic, and morph metric techniques will be employed. Second, the RYGB-induced alterations in the metabolic rate of the adipose tissue will be elucidated by measuring respiration rate in ex vivo tissue explants cultures. The specific aim 2 is also composed of two sub aims. First, the origin of the brown fat cells that appear in WAT proceeding RYGB will be identified. The approach is to label the proliferating pre-adiposities with BrdU and determine if the label propagates into the novel brown fat cells. Secondly, the key genes and molecular pathways involved in WAT and BAT remodeling will be identified through genome-wide expression. Lastly, in the specific aim 3, the contribution of brown adiposities in the post-surgical regulation of energy homeostasis will be determined. To do so, UCP1 knockout mice will be employed and RYGB-induced alterations in the in vivo metabolic rate, WAT and BAT phenotypes as well as WAT- and BAT-specific energy expenditures will be assessed and compared to those in their wild-type counterparts. With respect to expected outcomes, we anticipate that through induction and activation of brown adiposities, RYGB induces dramatic phenotypic and metabolic alterations in WAT and BAT. These alterations correlate with post-surgical augmentation of energy expenditure and hampering the brown adiposities induction blunts the therapeutic effects of the surgery significantly. PUBLIC HEALTH RELEVANCE: The future of the health of the population of the United States depends on identifying and providing effective treatment strategies for obesity. This proposal aims to shed light on the role of adipose tissue in regulating the metabolic rate and body weight after RYGB as well as the molecular pathways involved. The results will provide new target for the development of anti-obesity drugs.