Department of Cellular Biology, Institute of Biomedicine, Jinan University, Guangzhou, China.
Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.
FEBS J. 2024 Sep;291(18):4096-4110. doi: 10.1111/febs.17228. Epub 2024 Jul 23.
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.
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肽（PACAP）在能量代谢中起着重要作用，具有减轻胰岛素抵抗的潜力。然而，其确切机制尚不完全清楚。我们分别使用棕榈酸和高脂肪饮食（HFD）在 Alpha 小鼠肝 12 细胞系和 C57BL/6 小鼠中建立胰岛素抵抗模型，然后在体内和体外评估 PACAP 的作用。慢病毒载体用于探索 PACAP 可能改善胰岛素抵抗的信号通路。研究发现，PACAP 选择性结合 PACAP 型 I 受体受体，改善胰岛素抵抗，其特征是在胰岛素抵抗细胞模型和 HFD 喂养的小鼠中增加糖原合成和抑制糖异生。这些作用与 Fas 凋亡抑制分子/雷帕霉素不敏感的哺乳动物靶标 rapamycin 的伴侣/RAC-α丝氨酸/苏氨酸蛋白激酶（FAIM/Rictor/AKT）轴的激活有关。此外，PACAP 通过增加溶质载体家族 2、促进葡萄糖转运蛋白 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 在体内和体外均促进了肝 AKT/糖原合酶激酶 3β的磷酸化。此外，PACAP 处理可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 通过 FAIM/Rictor/AKT 轴改善胰岛素抵抗，为治疗肥胖相关胰岛素抵抗提供了一种有前途的药物候选物。
