Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice
Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice
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DOI：
10.1016/j.biomaterials.2020.119839
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发表时间：
2020-05-01
期刊：
影响因子：
14
通讯作者：
Ziouzenkova, Ouliana
中科院分区：
文献类型：
--
作者：
Lee, Aejin;Sun, Yuan;Ziouzenkova, Ouliana
外周组织和神经组织中葡萄糖摄取的差异导致神经组织中胰岛素的功效降低。在此，我们报告了短肽的设计，称为带有或不带有修饰侧链部分的氨基酸化合物（AAC）。在纳摩尔浓度下，含有 7-（二乙氨基）香豆素-3-甲酰胺侧链的候选治疗分子 AAC2 通过激活胰岛素不敏感葡萄糖转运蛋白 1 (GLUT1) 改善人外周脂肪细胞和内皮脑屏障细胞的葡萄糖控制。 AAC2 与瘦素受体 (LepR) 特异性相互作用，并激活非典型蛋白激酶 C zeta (PKC sigma) 以增加葡萄糖摄取。 AAC2 诱导的作用在瘦素受体缺陷的前脂肪细胞和 Lepr(db) 小鼠中不存在。相比之下，AAC2 建立了血糖控制，改变了瘦素缺乏的 Lep(ob) 小鼠的食物摄入量。因此，AAC2 激活 LepR 并以与瘦素不同的细胞因子样方式发挥作用。在与 1 型糖尿病相关表型的单基因 Ins2(Akita) 小鼠模型中，AAC2 挽救了这些小鼠的全身葡萄糖摄取，而没有增加胰岛素水平和肥胖，正如在胰岛素治疗的 Ins2(Akita) 小鼠中所见。与胰岛素相比，AAC2 治疗增加了 ins2(Akita) 小鼠的脑质量并减少了焦虑相关行为。我们的数据表明，AAC2 的独特作用机制（激活 LepR/PKC sigma/GLUT1 轴）提供了一种有效的策略来扩大血糖控制，以预防神经系统以及可能的其他胰岛素不敏感或抵抗组织的糖尿病并发症。
Differences in glucose uptake in peripheral and neural tissues account for the reduced efficacy of insulin in nervous tissues. Herein, we report the design of short peptides, referred as amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of insulin-insensitive glucose transporter 1 (GLUT1). AAC2 interacted specifically with the leptin receptor (LepR) and activated atypical protein kinase C zeta (PKC sigma) to increase glucose uptake. The effects induced by AAC2 were absent in leptin receptor-deficient predipocytes and in Lepr(db) mice. In contrast, AAC2 established glycemic control altering food intake in leptin-deficient Lep(ob) mice. Therefore, AAC2 activated the LepR and acted in a cytokine-like manner distinct from leptin. In a monogenic Ins2(Akita) mouse model for the phenotypes associated with type 1 diabetes, AAC2 rescued systemic glucose uptake in these mice without an increase in insulin levels and adiposity, as seen in insulin-treated Ins2(Akita) mice. In contrast to insulin, AAC2 treatment increased brain mass and reduced anxiety-related behavior in ins2(Akita) mice. Our data suggests that the unique mechanism of action for AAC2, activating LepR/PKC sigma/GLUT1 axis, offers an effective strategy to broaden glycemic control for the prevention of diabetic complications of the nervous system and, possibly, other insulin insensitive or resistant tissues.