PACAP通过FAIM/Rictor/AKT轴改善肥胖引起的胰岛素抵抗。

Jia Feng, Wenhui Chen, Shanshan Li, Qianchen Fang, Xingwu Chen, Ge Bai, Meng Tian, Yongmei Huang, Pei Xu, Zixian Wang, Yi Ma
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引用次数: 0

摘要

肥胖和肥胖相关的胰岛素抵抗一直是研究热点。垂体腺苷酸环化酶激活多肽(PACAP)在能量代谢中发挥着重要作用,有望减轻胰岛素抵抗。然而,其确切机制尚不完全清楚。我们利用棕榈酸和高脂饮食(HFD)分别在阿尔法小鼠肝12细胞系和C57BL/6小鼠中建立了胰岛素抵抗模型。随后,我们评估了 PACAP 在体内和体外的作用。我们使用慢病毒载体探索了PACAP可能改善胰岛素抵抗的信号通路。研究发现,PACAP 能选择性地与 PACAP I 型受体结合,并能改善胰岛素抵抗,其特点是在胰岛素抵抗细胞模型和高密度脂蛋白喂养的小鼠中,糖原合成增加,葡萄糖生成受到抑制。这些作用与雷帕霉素/RAC-α丝氨酸/苏氨酸蛋白激酶(FAIM/Rictor/AKT)轴的Fas凋亡抑制分子/雷帕霉素不敏感伴侣的激活有关。此外,PACAP还通过增加溶质运载家族2、促进葡萄糖转运体成员2/4和抑制葡萄糖生成相关蛋白葡萄糖6-磷酸酶催化亚基1和磷酸烯醇丙酮酸羧激酶2的表达来改善胰岛素抵抗。同时,PACAP在体内和体外都促进了肝脏AKT/糖原合成酶激酶3β的磷酸化。此外,PACAP 还能降低肥胖小鼠的体重、食物摄入量和血糖水平。我们的研究表明,PACAP可通过FAIM/Rictor/AKT轴改善胰岛素抵抗,是治疗肥胖相关胰岛素抵抗的有望候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

PACAP ameliorates obesity-induced insulin resistance through FAIM/Rictor/AKT axis

PACAP ameliorates obesity-induced insulin resistance through FAIM/Rictor/AKT axis

Obesity and obesity-related insulin resistance have been a research hotspot. Pituitary adenylate cyclase activating polypeptide (PACAP) has emerged as playing a significant role in energy metabolism, holding promising potential for attenuating insulin resistance. However, the precise mechanism is not fully understood. Palmitic acid and a high-fat diet (HFD) were used to establish insulin resistance model in Alpha mouse liver 12 cell line and C57BL/6 mice, respectively. Subsequently, we assessed the effects of PACAP both in vivo and in vitro. Lentivirus vectors were used to explore the signaling pathway through which PACAP may ameliorate insulin resistance. PACAP was found to selectively bind to the PACAP type I receptor receptor and ameliorate insulin resistance, which was characterized by increased glycogen synthesis and the suppression of gluconeogenesis in the insulin-resistant cell model and HFD-fed mice. These effects were linked to the activation of the Fas apoptotic inhibitory molecule/rapamycin-insensitive companion of mammalian target of rapamycin/RAC-alpha serine/threonine-protein kinase (FAIM/Rictor/AKT) axis. Furthermore, PACAP ameliorated insulin resistance by increasing solute carrier family 2, facilitated glucose transporter members 2/4 and inhibiting gluconeogenesis-related proteins glucose 6-phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 2 expression. Meanwhile, the phosphorylation of hepatic AKT/glycogen synthase kinase 3β was promoted both in vivo and in vitro by PACAP. Additionally, PACAP treatment decreased body weight, food intake and blood glucose levels in obese mice. Our study shows that PACAP ameliorated insulin resistance through the FAIM/Rictor/AKT axis, presenting it as a promising drug candidate for the treatment of obesity-related insulin resistance.

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