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

• DOI: 10.1038/s41467-022-34258-w
• Publication Date: 2022-10-27T15:22:48Z
• Authors: 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; Hao Ying
• Keywords: 0301 basic medicine; Thyroid Hormones; Science; Q; Receptors, Cytoplasmic and Nuclear; Article; Receptors, G-Protein-Coupled; Bile Acids and Salts; Mice, Inbred C57BL; Mice; Fragile X Mental Retardation Protein; 03 medical and health sciences; Glucose; Liver; Glucagon-Like Peptide 1; Animals; Homeostasis; Insulin

AbstractThyroid 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.