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| Status |
Public on Apr 30, 2021 |
| Title |
Inducible hepatic expression of CREBH mitigates diet-induced obesity, insulin resistance and hepatice steatosis in mice. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is a transcription factor that regulates the expression of genes that control lipid and glucose metabolism, as well as inflammation. CREBH is upregulated in the liver under conditions of overnutrition, and mice globally lacking the gene (CREBH-/-) are highly susceptible to diet-induced obesity, insulin resistance (IR) and hepatic steatosis. The net protective effects of CREBH have been attributed in large part to the activities of Fibroblast growth factor (Fgf)-21 (Fgf21), a target gene that promotes weight loss, improves glucose homeostasis and reduces hepatic lipid accumulation. To explore the possibility that activation of the CREBH-Fgf21 axis could ameliorate established effects of high fat feeding, we generated an inducible transgenic hepatocyte-specific CREBH overexpression mouse model (Tg-rtTA). Acute overexpression of CREBH in livers of Tg-rtTA mice effectively reversed diet-induced obesity, IR and hepatic steatosis. These changes were associated with increased activities of thermogenic brown and beige adipose tissues in Tg-rtTA mice, leading to reductions in fat mass, along with enhanced insulin sensitivity and glucose tolerance. Genetically silencing of Fgf21 in Tg-rtTA mice abrogated the CREBH-mediated reductions in body weight loss, but only partially reversed the observed improvements in glucose metabolism. These findings reveal that the protective effects of CREBH activation may be leveraged to mitigate diet-induced obesity and associated metabolic abnormalities in both Fgf21-dependent and -independent pathways.
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| Overall design |
Hepatocytes were transduced with adenoviruses encoding green fluorescent protein (Ad-GFP; Control) or nuclear CREBH (Ad-nuclear CREBH), and 24 hrs later gene expression was profiled.
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| Contributor(s) |
Krumm CS, Xu X, Bare CJ, Holman CD, Kersten S, Dow LE, Lee A, Cohen DE |
| Citation(s) |
34023388 |
| Submission date |
Apr 29, 2021 |
| Last update date |
Jul 30, 2021 |
| Contact name |
Guido Hooiveld |
| E-mail(s) |
guido.hooiveld@wur.nl
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| Organization name |
Wageningen University
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| Department |
Div. Human Nutrition & Health
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| Lab |
Nutrition, Metabolism & Genomics Group
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| Street address |
HELIX, Stippeneng 4
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| City |
Wageningen |
| ZIP/Postal code |
NL-6708WE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (6)
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| GSM5269526 |
Primary hepatocytes, Ad-GFP, replicate1 |
| GSM5269527 |
Primary hepatocytes, Ad-GFP, replicate2 |
| GSM5269528 |
Primary hepatocytes, Ad-GFP, replicate3 |
| GSM5269529 |
Primary hepatocytes, Ad-CREBH3, replicate1 |
| GSM5269530 |
Primary hepatocytes, Ad-CREBH3, replicate2 |
| GSM5269531 |
Primary hepatocytes, Ad-CREBH3, replicate3 |
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| Relations |
| BioProject |
PRJNA726146 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE173548_RAW.tar |
26.7 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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