Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
复制标题
DOI：
10.1073/pnas.1406000111
复制
发表时间：
2014-08-12
影响因子：
11.1
通讯作者：
Diano, Sabrina
中科院分区：
文献类型：
--
作者：
Kim, Jung Dae;Toda, Chitoku;Diano, Sabrina
脯氨酰内肽酶（PREP）与神经元功能有关。在这里，我们报告说，下丘脑PREP主要表达在腹内侧核（VMH），在那里它调节葡萄糖诱导的神经元激活。与野生型对照组相比，PREP敲低小鼠（Prep（gt/gt））表现出葡萄糖耐受不良、空腹胰岛素降低、空腹胰高血糖素水平升高和葡萄糖诱导的胰岛素分泌减少。与此相一致，在野生型小鼠中，特异性PREP抑制剂S17092的中枢输注损害葡萄糖耐量并降低胰岛素水平。进一步论证了PREP的中枢作用模式，分离的胰岛在葡萄糖诱导的胰岛素释放方面在Prep（gt/gt）和野生型小鼠之间没有差异。此外，高胰岛素正葡萄糖钳夹研究显示Prep（gt/gt）和野生型对照小鼠之间没有差异。胰岛素和胰高血糖素分泌的中枢PREP调节似乎是由自主神经系统介导的，因为Prep（gt/gt）小鼠胰腺中的交感神经流出和去甲肾上腺素水平升高，普萘洛尔治疗逆转了这些小鼠的葡萄糖耐受不良。最后，通过双侧VMH注射腺相关病毒-PREP重新表达PREP逆转了Prep（gt/gt）小鼠的葡萄糖不耐受表型。总之，我们的研究结果揭示了一个以前未知的球员在中央调节葡萄糖代谢和胰腺功能。
Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prep(gt/gt)) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prep(gt/gt) and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prep(gt/gt) and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prep(gt/gt) mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus-PREP reversed the glucose-intolerant phenotype of the Prep(gt/gt) mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.