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| Status |
Public on Aug 16, 2019 |
| Title |
Glucagon-receptor signaling regulates energy metabolism via hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast-growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from GcgR-activation, prompting us to search for additional pathways. Intriguingly, chronic GcgR agonism increases plasma bile acid levels. We hypothesized that GcgR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole body and liver-specific FXR knockout (FXR∆liver) mice. Chronic GcgR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21 and Fxr whole body or liver-specific knockout (∆liver) mice failed to reduce body weight (BW) when compared to wildtype (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not FXR∆liver mice. GcgR agonism increased [14C]-palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from FXR∆liver mice. Our data clearly demonstrate that control of whole body energy expenditure by GcgR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in the therapy of metabolic disorders.
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| Overall design |
RNA sequencing analysis of mice given IUB288 or vehicle treatment. Fxr-floxed mice were were used relative to wild-type controls. All mice were vmaintained on a C57Bl/6J background.
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| Web link |
https://diabetes.diabetesjournals.org/content/67/9/1773.long
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| Contributor(s) |
Pepin ME, Kim T, Nason S, Holleman C, Wilson L, Berryhill T, Wende AR, Steele C, Young M, Barnes S, Drucker D, Finan B, DiMarchi R, Perez-Tilve D, Tschoep M, Habegger KM |
| Citation(s) |
29925501 |
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| Submission date |
Aug 15, 2019 |
| Last update date |
Nov 15, 2019 |
| Contact name |
Mark Emile Pepin |
| E-mail(s) |
pepinme@gmail.com
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| Organization name |
University of Alabama at Birmingham
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| Department |
Biomedical Engineering
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| Lab |
Adam Wende Laboratory
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| Street address |
1825 University Blvd
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| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35294-2182 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (8)
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| GSM4037073 |
Liver, 131KO, Vehicle |
| GSM4037074 |
Liver, 122KO, IUB288 |
| GSM4037075 |
Liver, 106KO, IUB288 |
| GSM4037076 |
Liver, 102WT, IUB288 |
| GSM4037077 |
Liver, 98WT, Vehicle |
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| Relations |
| BioProject |
PRJNA560395 |
| SRA |
SRP218456 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE135881_IUB288_KO_vs_IUB288_WT_gene_differential_expression.xlsx |
4.7 Mb |
(ftp)(http) |
XLSX |
| GSE135881_IUB288_KO_vs_Veh_KO_gene_differential_expression.xlsx |
5.2 Mb |
(ftp)(http) |
XLSX |
| GSE135881_IUB288_WT_vs_Veh_WT_gene_differential_expression.xlsx |
5.3 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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