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| Status |
Public on Aug 10, 2023 |
| Title |
RNA-seq of metformin treatment in liver in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high fat diet treated with metformin was largely ablated by AMPK-deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.
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| Overall design |
Mice maintained on 45% high fat diet for 12 weeks, fasted overnight, refed for 1h, and treated with 200 mpk metformin or saline for 4 hours
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| Contributor(s) |
Van Nostrand JL, Shaw RJ, Hellberg K, Luo E, Van Nostrand EL, Dayn A, Yu J, Shokhirev MN, Dayn Y, Yeo GW |
| Citation(s) |
32912901 |
| |
| Submission date |
Aug 28, 2020 |
| Last update date |
Aug 10, 2023 |
| Contact name |
April Elizabeth Williams |
| E-mail(s) |
apriljack06@gmail.com, awilliams@salk.edu
|
| Phone |
7345461645
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| Organization name |
Salk Institute for Biological Studies
|
| Department |
IGC
|
| Street address |
10010 N Torrey Pines Rd
|
| City |
San Diego |
| State/province |
California |
| ZIP/Postal code |
92037 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (29)
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| This SubSeries is part of SuperSeries: |
| GSE157051 |
AMPK regulation of Raptor and TSC2 mediate Metformin effects on transcriptional control of anabolism and inflammation |
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| Relations |
| BioProject |
PRJNA659988 |
| SRA |
SRP279198 |
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