Role of pancreatic neuropeptide Y in obesity and diabetes

描述(由申请人提供)： 胰岛对胰岛素抵抗的适应在肥胖患者维持正常血糖方面起着关键作用(1)。然而，在一些患者中，胰岛适应减弱，导致糖尿病的发病(2)。目前，胰岛适应肥胖的潜在机制还不是很清楚。有趣的是，神经肽Y(NPY)，一种已知在肥胖发展中起重要作用的在大脑中的肽，也在胰岛中被发现，并可能整合能量平衡和血糖平衡。肥胖、胰岛素抵抗、高胰岛素血症小鼠胰腺NPY及其受体的表达显著降低。此外，NPY缺乏的胰岛更大，有更高的胰岛素分泌，这意味着NPY通过旁分泌或自分泌机制抑制胰岛素分泌(3)。因此，我们推测肥胖时胰腺NPY的抑制可能是增加胰岛素分泌，预防糖尿病发展为胰岛素抵抗状态的机制之一。 为了验证这一假设，将建立在肥胖发生过程中维持胰岛NPY表达并防止NPY下调的小鼠模型。NPY转基因的表达水平旨在达到与非肥胖小鼠的生理水平相当的水平。然后将小鼠置于高脂饮食中，以研究在饮食诱导的肥胖中，阻止胰岛NPY下调是否干扰胰岛素分泌的增强，并加速糖尿病的发展。其次，阐明NPY对胰岛素分泌和存活的补益作用。将含有NPY基因的腺病毒感染NPY基因缺失小鼠的胰岛，在培养条件下实现对NPY的慢性暴露。此后，将比较NPY腺病毒转导的胰岛和对照胰岛在葡萄糖刺激下的胰岛素分泌和细胞凋亡。这项研究是首席研究员正在进行的项目的扩展，得到了K08赠款的支持，该项目解决了NPY在利用NPY缺陷小鼠调节胰岛素分泌方面的中枢和胰腺作用。这些研究旨在解决NPY在血糖稳态中的作用，并有可能揭示一种新的机制，以防止肥胖糖尿病的发展。 除了加深我们对肥胖症中胰岛适应的了解外，该项目还将为首席研究员Imai博士提供关键资金，以提高她在研究方面的独立性，并建立她在糖尿病/内分泌学方面的学术生涯。NPY转基因模型有很大的潜力发展成为未来R01应用的新项目。这项研究将在宾夕法尼亚大学糖尿病、肥胖和新陈代谢研究所以及内分泌学、糖尿病和新陈代谢系进行，由Rexford Ahima博士和Franz Matschinsky博士监督。该研究所在糖尿病和肥胖症研究方面拥有专业知识，并将为实施拟议的项目提供出色的环境。 公共卫生相关性：该项目将探讨胰岛神经肽Y在调节胰岛素分泌和葡萄糖稳态中的作用。这项研究有可能揭示一种新的机制，以增加肥胖症患者的胰岛素分泌，防止肥胖患者发展为糖尿病。

DESCRIPTION (provided by applicant): Adaptation of pancreatic islets to insulin resistance plays critical role in the maintenance of normoglycemia in obesity (1). However, in some patients islet adaptation is attenuated, leading to the onset of diabetes (2). Currently the underlying mechanisms for islet adaptation to obesity are not well understood. Interestingly Neuropeptide Y (NPY), a peptide in the brain that is known to play an important role in the development of obesity, is also found in the pancreatic islets and may integrate energy homeostasis and glucose homeostasis (3). The expression of pancreatic NPY and its receptor is markedly decreased in obese, insulin resistant, hyperinsulinemic mice (3). Moreover NPY deficient islets are larger and have higher insulin secretion implying that NPY acts through a paracrine or autocrine mechanism to tonically inhibit insulin secretion (3). Therefore it is hypothesized that the suppression of pancreatic NPY seen in obesity serves as one of the mechanisms to increase insulin secretion and prevents the development of diabetes in insulin resistant status. To test the hypothesis the mouse model that maintains the expression of NPY transgenically in islets and is prevented from the down-regulation of NPY during the development of obesity will be established. The expression level of NPY transgene is aimed at the level comparable to the physiological level seen in non-obese mouse. Then the mouse will be placed on high fat diet to address whether the prevention of down-regulation of NPY in the pancreatic islets interferes with the enhancement of insulin secretion and accelerates the development of diabetes in diet-induced obesity. Secondly the tonic effects of NPY on insulin secretion and its survival will be clarified. Pancreatic islets from Npy null mice will be infected with adenovirus containing NPY cDNA to achieve chronic exposure to NPY in culture. Thereafter glucose-stimulated insulin secretion and apoptosis will be compared between islets transduced with NPY adenovirus and control. The study is the expansion of the on going project by the principal investigator supported by a K08 grant that addresses both central and pancreatic role of NPY in the regulation of insulin secretion using NPY deficient mice. These study aim to address the role of NPY in glucose homeostasis and have potential to reveal a new mechanism that prevents the development of diabetes in obesity. In addition to deepening our knowledge of islet adaptation in obesity, the project will provide crucial funding for the principal investigator, Dr. Imai, to increase her independency in research and to establish her academic career in Diabetes/Endocrinology. The NPY transgene model has a great potential to develop into a new project for future R01 application. The study will be carried out in the Institute of Diabetes, Obesity and Metabolism and the Division of Endocrinology, Diabetes, and Metabolism at the University of Pennsylvania under the supervision of Dr. Rexford Ahima and Dr. Franz Matschinsky. The institute has expertise in diabetes and obesity research, and will provide outstanding environment to conduct the proposed project. PUBLIC HEALTH RELEVANCE: The project will address the role of neuropeptide Y in pancreatic islets in the regulation of insulin secretion and glucose homeostasis. The study has a potential to reveal a new mechanism to increase insulin secretion in obesity and prevent the development of diabetes in obesity.