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.
© 2022. The Author(s).