Pancreatic Neural Circuitry in Obesity and Diabetes

项目概要/摘要： 肥胖症在美国非常普遍，线性趋势预测表明，超过50%的 到20301年，人口将遭受肥胖症的困扰。肥胖会增加患慢性病的风险 2型糖尿病（T2 D）。肥胖和糖尿病的生物学，以及 它们之间的联系是复杂的，而且人们对其了解甚少，这影响了我们有效治疗T2 D的能力。只 三分之一的糖尿病患者血糖得到了充分控制，这表明需要更有效的 治疗1，35.进一步研究肥胖对内分泌胰腺的影响势在必行， 了解T2 D的病因和发病机制，这可能为未来的机制和 药理学研究旨在预防和治疗T2 D。胰腺，尤其是胰岛， 在糖尿病和肥胖症中，神经支配和神经密度异常。然而，由于先前发表的研究 主要使用2D成像和极端肥胖模型，我们没有详细的胰腺映射， 在临床相关模型中的神经支配。我们的方法将克服这些局限性， HFD对透明组织中胰腺神经支配的结构和区域变化的影响。我们的初步研究 表明60%HFD增加小鼠胰岛内交感神经支配，也可能降低 副交感神经支配由于结构和功能相关，确定HFD如何影响神经 结构将为HFD对胰岛功能的影响提供新的见解。神经信号的重要性 控制胰腺激素释放已在包括人类在内的许多物种中显示。但不少 研究使用神经刺激策略，影响多个器官，感觉和运动通路，因此， 尚不清楚胰腺内的神经信号是否影响胰岛激素分泌。我们的初步研究显示 胰腺副交感神经元的特异性激活改善葡萄糖刺激的胰岛素分泌， 并且显著降低了HFD喂养3天和7天后GTT期间的血糖水平（45%）。我们 初步研究强烈支持HFD增加胰岛交感神经活性并降低 胰岛副交感神经活动，导致胰岛素不足以维持正常血糖。这一假设 将在以下目标中进行测试：目标1-使用iDisco+，一种整体免疫标记技术， 结合高分辨率成像，以确定HFD对胰岛3D结构的影响 交感神经和副交感神经。目的2-利用DREADD技术调节胰腺细胞的活性， 神经，并确定HFD对胰岛激素分泌的副交感神经和交感神经控制的影响。 本研究的结果将确定正常人胰腺神经细胞群的结构和功能。 生理学和高脂饮食喂养后，最终提供了新的见解的机制， T2 D的病理生理学，这可以促进旨在预防T2 D的更有效疗法的开发。 和T2 D的治疗。

Project Summary/Abstract: Obesity is extremely prevalent in the United States, and linear trend forecasts suggest that more than 50% of the population will suffer from obesity by 20301. Obesity increases the risks for developing chronic health conditions, such as Type 2 diabetes (T2D). The biology of obesity and diabetes, as well as the mechanisms linking them, are complex and poorly understood, which has impacted our abilities to effectively treat T2D. Only one third of people living with diabetes achieve adequate glycemic control, suggesting a need for more effective therapies1,35. Further investigation into the impact of obesity on the endocrine pancreas is imperative to understanding the etiology and pathogenesis of T2D, which may provide a foundation for future mechanistic and pharmacological studies aimed at preventing and treating T2D. The pancreas, and especially islets, are richly innervated and nerve density is abnormal in diabetes and obesity. However, since previously published studies predominantly use 2D imaging and extreme models of obesity, we do not have detailed mapping of pancreatic innervation in a clinically relevant model. Our approach will overcome these limitations by determining the effect of a HFD on structural and regional changes in pancreas innervation in cleared tissue. Our preliminary studies indicate that a 60% HFD increases sympathetic innervation within mouse islets, and may also decrease parasympathetic innervation. Since structure and function are related, determining how a HFD impacts nerve structure will provide novel insight into the effect of a HFD on islet function. The importance of neural signals in controlling pancreatic hormone release has been shown in many species, including humans. However, many studies use nerve stimulation strategies, which impact multiple organs, and sensory and motor pathways, so it is unknown if neural signaling within the pancreas impacts islet hormone secretion. Our preliminary studies show that the specific activation of pancreatic parasympathetic neurons improves glucose stimulated insulin secretion, and significantly reduces plasma glucose levels during a GTT after 3 and 7 days of HFD feeding (45%). Our preliminary studies strongly support the hypothesis that a HFD increases islet sympathetic activity and decreases islet parasympathetic activity, leading to insufficient insulin to maintain normal plasma glucose. This hypothesis will be tested in the following aims: Aim 1- to use iDisco+, a whole mount immunolabeling technique, in conjunction with high resolution imaging, to determine the effects of a HFD on the 3D structure of islet sympathetic and parasympathetic nerves. Aim 2- To utilize DREADD technology to regulate activity in pancreatic nerves and determine the effect of a HFD on parasympathetic and sympathetic control of islet hormone secretion. The findings of this proposal will determine the structure and function of pancreatic neural populations in normal physiology and after high fat diet feeding, ultimately providing new insight into the mechanisms and pathophysiology of T2D, which can promote the development of more effective therapies aimed at the prevention and treatment of T2D.