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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 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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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 two groups, fasting and feeding, one sample per group, and each sample is the pool of livers of three mice treated the same.
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| Contributor(s) |
Liu W, 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 |
| BioProject |
PRJNA762511 |
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| Submission date |
Sep 13, 2021 |
| Last update date |
Nov 02, 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) |
| GPL10333 |
Agilent-026655 Whole Mouse Genome Microarray 4x44K v2 (Feature Number version) |
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| Samples (2) |
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| Supplementary file |
Size |
Download |
File type/resource |
| GSE184055_RAW.tar |
10.8 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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