Molecular and Cellular Basis for the Efficacy of Bariatric Surgery

描述（由申请人提供）：减肥手术是目前唯一有效治疗严重肥胖的方法，也是唯一有效治愈II型糖尿病的方法。在人类和模型系统（包括猪、犬、大鼠和小鼠）中对不同减肥手术的作用机制进行的研究支持了以下假设，即有益作用不仅仅是由于手术对食物摄入的限制或吸收不良作用。事实上，数据表明，Roux-en-Y和袖状胃手术导致的肠-脑信号传导的神经内分泌变化在实现显著体重减轻之前改变了饱腹感、饥饿感、食物偏好和葡萄糖稳态。了解减肥手术引起的这些变化的细胞和分子基础可能会导致药物干预的发展，或改善治疗肥胖和糖尿病的外科手术。虽然有几种动物模型可用于减肥手术的生理学研究，但小鼠为细胞和分子机制的研究提供了最佳模型，因为转基因可用于改变单个基因，并标记特定的细胞类型。我们在这里展示的结果证明了在范德比尔特成功建立了鼠减肥手术模型，并使用该模型鉴定了在RYGB长期维持显著体重减轻的功效中起重要作用的第一个基因。待检验的独特假设是减肥手术的功效不仅来自于GI信号传导的变化的集合，而是GI信号传导和CNS稳态和享乐回路的可塑性和响应性的基本变化协同作用以恢复葡萄糖稳态，并产生新的体重设定点。在这个跨学科的团队资助申请中，我们汇集了人类和小鼠减肥手术，小鼠病理学，GI解剖学和功能，肥胖和糖尿病以及定量人类遗传学方面的领先专家，共同研究人类和小鼠的手术制剂，以确定介导减肥手术疗效的基因和细胞类型。

DESCRIPTION (provided by applicant): Bariatric surgery is currently the only effective treatment for severe obesity, and the only effective cure for type II diabetes. Research on the mechanism of action of the different bariatric surgical procedures in humans and model systems including pigs, dogs, rats, and mice supports the hypothesis that the beneficial effects result from more than the restrictive or malabsorptive effects of the procedures on food intake. Indeed, data argue that neuroendocrine changes in gut-brain signaling resulting from the Roux-en-Y and gastric sleeve procedures alter satiety, hunger, food preferences, and glucose homeostasis prior to the achievement of significant weight loss. Understanding the cellular and molecular basis of these changes induced by bariatric surgery might lead to the development of pharmaceutical interventions, or improved surgical procedures for the treatment of obesity and diabetes. While several animal models can be used for research on the physiology of bariatric surgery, the mouse provides the best model for studies of cellular and molecular mechanisms because transgenesis can be used to alter individual genes, and to label specific cell types. We show results here demonstrating successful creation of murine bariatric surgery models at Vanderbilt, and the use of the models to identify the first gene that plays an essential role in th efficacy of RYGB for long term maintenance of significant weight loss. The unique hypothesis to be tested is that the efficacy of bariatric surgery results not solely from a collection of changesto Gl signaling, but rather that essential changes in both Gl signaling AND in the plasticity and responsiveness of CNS homeostatic and hedonic circuits act synergistically to restore glucose homeostasis, and create a new weight set point. In this interdisciplinary team grant application, we bring together leading experts in human and murine bariatric surgery, murine pathology, Gl anatomy and function, obesity and diabetes, and quantitative human genetics to jointly study surgical preparations from humans and mice in order to identify the genes and cell types mediating the efficacy of bariatric surgery.