Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism

Ying Yan, Zhoumin Niu, Chao Sun, Peng Li, Siyi Shen, Shengnan Liu, Yuting Wu, Chuyu Yun, Tingying Jiao, Sheng Jia, Yuying Li, Zhong-Ze Fang, Lin Zhao, Jiqiu Wang, Cen Xie, Changtao Jiang, Yan Li, Xiaoyun Feng, Cheng Hu, Jingjing Jiang () and Hao Ying ()
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Ying Yan: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Zhoumin Niu: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Chao Sun: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Peng Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Siyi Shen: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Shengnan Liu: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Yuting Wu: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Chuyu Yun: Peking University
Tingying Jiao: Chinese Academy of Sciences
Sheng Jia: Shanghai Jiao Tong University School of Medicine
Yuying Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Zhong-Ze Fang: Tianjin Medical University
Lin Zhao: Fudan University
Jiqiu Wang: Shanghai Jiao Tong University School of Medicine
Cen Xie: Chinese Academy of Sciences
Changtao Jiang: Peking University
Yan Li: Jiangnan University
Xiaoyun Feng: Shanghai Jiaotong University
Cheng Hu: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Jingjing Jiang: Fudan University
Hao Ying: University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34258-w

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