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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis
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Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis

机译：Urocortin 3调节葡萄糖刺激的胰岛素分泌和能量稳态

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摘要

Urocortin 3 (Ucn 3), a member of the corticotropin-releasing factor (CRF) family of peptides, is strongly expressed in mammalian pancreatic β cells and has been shown to stimulate insulin secretion. Here we report the investigation of the hypothesis that endogenous Ucn 3 regulates insulin secretion, particularly in the presence of nutrient excess. Secretion of Ucn 3-like immunoreac-tivity from cultured β cells was stimulated by high glucose and insulin secretagogs such as GLP-1; furthermore, 5 pancreatic Ucn 3 mRNA levels in vivo were increased during the positive energy balance caused by high-fat diet and by the absence of leptin. Immunoneutralization of Ucn 3 or pharmacologic blockade of its receptor, the type 2 CRF receptor (CRFR2), attenuated high but not low glucose-induced insulin secretion from isolated islets in vitro. Cultured islets isolated from Ucn 3-null mice also secreted less insulin in response to high glucose-concentrations. Consistently, peripheral injection of a selective CRFR2 antagonist before the administration of a glucose challenge significantly attenuated glucose-induced insulin secretion in vivo. Ucn 3-null mice were relatively protected from the hyperinsulinemia, hypergtycemia, glucose intolerance, hepatic steatosis, and hypertriglyceridemia induced by high-fat diet. Additionally, we found that aged Ucn 3-null mice maintained better glucose tolerance than age-matched wild-type littermates. These results suggest that endogenous Ucn 3 in the pancreas is induced under excessive caloric conditions and acts locally to augment insulin production, which in the long-term may contribute to reduced insulin sensitivity and harmful metabolic consequences.
机译：促肾上腺皮质激素释放因子（CRF）家族成员Urocortin 3（Ucn 3）在哺乳动物胰腺β细胞中强烈表达，并已显示出可刺激胰岛素分泌。在这里，我们报告对内源性Ucn 3调节胰岛素分泌的假说的调查，尤其是在营养过剩的情况下。高葡萄糖和胰岛素分泌蛋白（例如GLP-1）刺激培养的β细胞分泌Ucn 3样免疫反应。此外，在高脂饮食和缺乏瘦素导致的正能量平衡期间，体内5种胰腺Ucn 3 mRNA水平增加。 Ucn 3的免疫原化或其受体2型CRF受体（CRFR2）的药理学阻断作用可减弱离体胰岛的高葡萄糖诱导的胰岛素分泌，但不能低。从Ucn 3-null小鼠分离的胰岛也响应高葡萄糖浓度而分泌较少的胰岛素。一致地，在给予葡萄糖激发之前外围注射选择性CRFR2拮抗剂显着减弱了体内葡萄糖诱导的胰岛素分泌。 Ucn 3-null小鼠相对免受高脂饮食诱导的高胰岛素血症，高血糖症，葡萄糖耐受不良，肝脂肪变性和高甘油三酸酯血症的侵害。此外，我们发现，与年龄相匹配的野生型同窝幼仔相比，Ucn 3无效的老年小鼠维持了更好的葡萄糖耐量。这些结果表明，胰腺中的内源性Ucn 3在过高的热量条件下被诱导，并在局部发挥作用，以增加胰岛素的产生，从长期来看，这可能有助于降低胰岛素敏感性和有害的代谢后果。

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