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

ABSTRACT: A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE184055 | GEO | 2022/09/23

REPOSITORIES: GEO

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Project description:Synthetic selective thyroid hormone (TH) receptor (TR) modulators (STRMs) exhibit beneficial effects on dyslipidemias in animals and humans and reduce obesity, fatty liver and insulin resistance in preclinical animal models. STRMs differ from native THs in preferential binding to the TRβ subtype versus TRα, increased uptake into liver and reduced uptake into other tissues. However, selective modulators of other nuclear receptors (NRs) exhibit important gene-selective actions which have been attributed to differential effects on receptor conformation and dynamics and these effects can have profound influences in animals and humans. While there are suggestions that STRMs could exhibit such gene-specific actions, the extent to which these effects are actually observed in vivo has not been explored. Here, we show that saturating concentrations of the main active form of TH, triiodothyronine (T3), and the prototype STRM GC-1 induce identical gene-sets in livers of euthyroid and hypothyroid mice and a human cultured hepatoma cell line that only expresses TRβ, HepG2. We find one case in which GC-1 exhibits a modest gene-specific reduction in potency versus T3, at angiopoietin-like factor 4 (ANGPTL4) in HepG2. Investigation of the latter effect confirms that GC-1 acts through TRβ to directly induce this gene. However, this gene-selective GC-1 activity is not related to unusual T3 response element (TRE) sequence, unlike previously documented promoter-selective STRM actions. Together, our data suggest that T3 and GC-1 exhibit almost identical gene regulation properties and that gene-selective actions of GC-1 and similar STRMs will be subtle and rare. We treated HepG2 with vehicle or 10nM ligand (T3 or GC1; n=3 / treatment), analyzing mRNA 24h post treatment [Affymetrix]. We also treated 9-week old euthyroid male C57/Bl6 mice with vehicle or ligand (T3 or GC-1) by a single oral gavage (n=5 per treatment) and also performed a similar study in which mice were first made hypothyroid by two week feeding on iodine deficient diet (n=3-4 per treatment), analyzing mRNA 24h post treatment [Illumina].

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

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