Programa de Pós-Graduação em Produtos Bioativos e Biociências, Universidade Federal do Rio de Janeiro, Campus UFRJ-Macaé, Macaé, RJ, Brazil.
Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP, Brazil.
Life Sci. 2021 Nov 15;285:120020. doi: 10.1016/j.lfs.2021.120020. Epub 2021 Oct 5.
The bile acid (BA), tauroursodeoxycholic acid (TUDCA) regulates glucose homeostasis; however, it is not clear whether its effects on insulin signaling are due to its direct interaction with the insulin receptor (IR) or through activation of the G-coupled BA receptor, TGR5. We, herein, investigated whether the actions of TUDCA on glucose homeostasis occur via IR or TGR5 activation.
Glucose homeostasis was evaluated in high-fat diet (HFD)-obese or control (CTL) mice, after 30 days or one intraperitoneal (ip) injection of 300 mg/kg TUDCA, respectively. Molecular docking was performed to investigate the potential binding of TUDCA on the IR and TGR5.
After 30 days of TUDCA treatment, HFD mice exhibited improvements in glucose tolerance and insulin sensitivity, which were abolished when these rodents received the IR antagonist, S961. Molecular docking experiments showed that TUDCA demonstrates high binding affinity for TGR5 and IR and strongly interacts with the insulin binding sites 1 and 2 of the IR. Consistent with this potential agonist activity of TUDCA on IR, CTL mice displayed increased hepatic phosphorylation of AKT after an ip injection of TUDCA. This effect was not associated with altered glycemia in CTL mice and was dependent on IR activation, as S961 prevented hepatic AKT activation by TUDCA. Furthermore, TUDCA activated the hepatic protein kinase A (PKA) and cAMP response element-binding protein (CREB) pathway in CTL mice, even after the administration of S961.
We provide novel evidence that TUDCA may be an agonist of the IR, in turn activating AKT and contributing, at least in part, to its beneficial effects upon glucose homeostasis.
胆酸（BA），牛磺熊脱氧胆酸（TUDCA）调节葡萄糖稳态；然而，其对胰岛素信号的影响是否归因于其与胰岛素受体（IR）的直接相互作用或通过激活 G 蛋白偶联 BA 受体 TGR5，目前尚不清楚。在此，我们研究了 TUDCA 对葡萄糖稳态的作用是否通过 IR 或 TGR5 激活发生。
分别在高脂肪饮食（HFD）肥胖或对照（CTL）小鼠中，在 30 天或单次腹腔内（ip）注射 300mg/kg TUDCA 后，评估葡萄糖稳态。进行分子对接以研究 TUDCA 与 IR 和 TGR5 的潜在结合。
在 TUDCA 治疗 30 天后，HFD 小鼠的葡萄糖耐量和胰岛素敏感性得到改善，当这些啮齿动物接受 IR 拮抗剂 S961 时，这些改善被取消。分子对接实验表明，TUDCA 对 TGR5 和 IR 具有高结合亲和力，并与 IR 的胰岛素结合位点 1 和 2强烈相互作用。与 TUDCA 对 IR 的这种潜在激动剂活性一致，CTL 小鼠在腹腔内注射 TUDCA 后表现出肝 AKT 的磷酸化增加。这种作用与 CTL 小鼠的血糖变化无关，并且依赖于 IR 激活，因为 S961 可防止 TUDCA 激活肝 AKT。此外，TUDCA 可激活 CTL 小鼠的肝蛋白激酶 A（PKA）和 cAMP 反应元件结合蛋白（CREB）途径，即使在给予 S961 后也是如此。
我们提供了新的证据表明，TUDCA 可能是 IR 的激动剂，进而激活 AKT，并至少部分有助于其对葡萄糖稳态的有益作用。
