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| Status |
Public on Sep 23, 2022 |
| Title |
Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism [RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
There are three groups, MMI, MMI+T3, and CT, three sample per group
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| Contributor(s) |
Yan Y, Niu Z, Sun C, Li P, Shen S, Liu S, Li Y, Fang Z, Zhao L, Jiang C, Jiang J, Ying H |
| Citation(s) |
36302774 |
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| Submission date |
Sep 16, 2021 |
| Last update date |
Nov 29, 2022 |
| Contact name |
ying yan |
| E-mail(s) |
yanying2017@sibs.ac.cn
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| Organization name |
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences
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| Street address |
320 Yueyang Road, Shanghai
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| City |
Shanghai |
| ZIP/Postal code |
200031 |
| Country |
China |
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| Platforms (1) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA763828 |
| SRA |
SRP337406 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE184261_CT.xlsx |
705.1 Kb |
(ftp)(http) |
XLSX |
| GSE184261_MMI_MMI+T3.xlsx |
990.4 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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