Molecular and Cellular Basis for the Efficacy of Bariatric Surgery

描述(申请人提供)：减肥手术是目前治疗严重肥胖症的唯一有效方法，也是治疗II型糖尿病的唯一有效方法。对不同的减肥手术在人类和模型系统(包括猪、狗、大鼠和小鼠)中的作用机制的研究支持这样的假说，即有益的影响不仅仅是由于手术对食物摄入量的限制或吸收不良的影响。事实上，数据表明，Roux-en-Y和胃袖手术导致的肠道-大脑信号的神经内分泌变化在实现显著减肥之前改变了饱腹感、饥饿感、食物偏好和葡萄糖稳态。了解减肥手术引起这些变化的细胞和分子基础可能会导致开发药物干预措施，或改进治疗肥胖症和糖尿病的手术程序。虽然可以使用几种动物模型来研究减肥手术的生理学，但小鼠为细胞和分子机制的研究提供了最好的模型，因为转基因可以用来改变单个基因，并标记特定的细胞类型。我们在这里展示了在Vanderbilt成功创建小鼠减肥手术模型的结果，并使用该模型识别了第一个在RYGB长期维持显著减肥效果中起关键作用的基因。需要检验的唯一假设是，减肥手术的疗效不仅源于Gl信号的一系列变化，而且Gl信号以及中枢神经系统稳态和享乐回路的可塑性和反应性的基本变化协同作用，恢复血糖稳态，并创造一个新的体重设定点。在这项跨学科的团队资助申请中，我们汇集了人类和小鼠减肥外科、小鼠病理学、Gl解剖和功能、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外科准备工作，以确定调节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.