Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism.
Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism.
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DOI：
10.1038/s41467-022-34258-w
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发表时间：
2022-10-27
影响因子：
16.6
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中科院分区：
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甲状腺激素（TH）通过不完全理解的机制调节全身葡萄糖代谢。在这里，我们表明，改善甲状腺功能减退小鼠T3治疗后的葡萄糖代谢伴随着胰高血糖素样肽-1（GLP-1）的生产和胰岛素分泌增加，而与GLP-1受体拮抗剂的共同治疗减弱T3对胰岛素和葡萄糖水平的影响。通过使用缺乏肝脏TH受体β（TRβ）和肝脏特异性TRβ选择性激动剂的小鼠，我们证明了TRβ介导的肝脏TH信号传导对于GLP-1产生的调节以及T3的促胰岛素和降糖作用都是必需的。此外，肝脏靶向TRβ-选择性激动剂的给药可增加GLP-1和胰岛素水平，并减轻饮食诱导的肥胖症中的高血糖症。从机制上讲，T3抑制Cyp 8b 1表达，导致法尼醇X受体（FXR）拮抗性胆汁酸水平增加，从而通过抑制肠道FXR信号传导增强GLP-1的产生和胰岛素分泌。在甲状腺功能正常的人群中，T3与血浆GLP-1和粪便FXR拮抗胆汁酸水平相关。因此，我们的研究揭示了肝脏TH信号传导通过胆汁酸介导的FXR拮抗作用调节GLP-1产生在葡萄糖稳态中的作用。甲状腺激素通过不完全理解的机制调节全身葡萄糖代谢。作者报告称，肝脏甲状腺激素受体β通过抑制肝脏CYP 8B 1表达和胆汁酸介导的肠道FXR信号传导抑制来调节GLP-1水平，从而介导甲状腺激素T3对全身葡萄糖稳态的影响。
Thyroid hormones (TH) regulate systemic glucose metabolism through incompletely understood mechanisms. Here, we show that improved glucose metabolism in hypothyroid mice after T3 treatment is accompanied with increased glucagon-like peptide-1 (GLP-1) production and insulin secretion, while co-treatment with a GLP-1 receptor antagonist attenuates the effects of T3 on insulin and glucose levels. By using mice lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is required for both the regulation of GLP-1 production and the insulinotropic and glucose-lowering effects of T3. Moreover, administration of a liver-targeted TRβ-selective agonist increases GLP-1 and insulin levels and alleviates hyperglycemia in diet-induced obesity. Mechanistically, T3 suppresses Cyp8b1 expression, resulting in increased the levels of Farnesoid X receptor (FXR)-antagonistic bile acids, thereby potentiating GLP-1 production and insulin secretion by repressing intestinal FXR signalling. T3 correlates with both plasma GLP-1 and fecal FXR-antagonistic bile acid levels in people with normal thyroid function. Thus, our study reveals a role for hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism. Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
8.8
作者：
Lin JZ;Martagón AJ;Cimini SL;Gonzalez DD;Tinkey DW;Biter A;Baxter JD;Webb P;Gustafsson JÅ;Hartig SM;Phillips KJ
通讯作者：
Phillips KJ
影响因子：
14.8
作者：
Chaudhari SN;Harris DA;Aliakbarian H;Luo JN;Henke MT;Subramaniam R;Vernon AH;Tavakkoli A;Sheu EG;Devlin AS
通讯作者：
Devlin AS
影响因子：
25.7
作者：
Mueller, Michaela;Thorell, Anders;Trauner, Michael
通讯作者：
Trauner, Michael
肠道 FXR 激动剂可促进脂肪组织褐变，减少肥胖和胰岛素抵抗。
影响因子：
82.9
作者：
通讯作者：
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