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AMPK regulation of Raptor and TSC2 mediate Metformin effects on transcriptional control of anabolism and inflammation

ABSTRACT: AMPK regulation of Raptor and TSC2 mediate Metformin effects on transcriptional control of anabolism and inflammation

PROVIDER: PRJNA659984 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12539800.fastq.gz	Fastqsanger.gz
	SRR12539900.fastq.gz	Fastqsanger.gz
	SRR12539801.fastq.gz	Fastqsanger.gz
	SRR12539901.fastq.gz	Fastqsanger.gz
	SRR12539802.fastq.gz	Fastqsanger.gz

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RNA-seq of metformin treatment in liver in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null

Project description: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.

2023-08-10 | GSE157049 | GEO

Ribosome profiling of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

Project description: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 primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the translational response to metformin.

2023-08-10 | GSE157050 | GEO

RNA-seq of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

Project description: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 primary hepatocytes and 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.

2023-08-10 | GSE157048 | GEO

RNA-seq of metformin treatment in liver in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant Tsc2-null, and Ampk-null

Project description:RNA-seq of metformin treatment in liver in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant Tsc2-null, and Ampk-null

| PRJNA659988 | ENA

RNA-seq of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant Tsc2-null, and Ampk-null cells

Project description:RNA-seq of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant Tsc2-null, and Ampk-null cells

| PRJNA659989 | ENA

Ribosome profiling of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant Tsc2-null, and Ampk-null cells

Project description:Ribosome profiling of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant Tsc2-null, and Ampk-null cells

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AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation.

Project description: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 Raptor AA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for both the translational and 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.

| S-EPMC7528705 | biostudies-literature

AMPK regulation of Raptor and TSC2 mediate Metformin effects on transcriptional control of anabolism and inflammation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-10 | GSE157051 | GEO

Conjugated linoleic acid activates AMPK and reduces adiposity more effectively when used with metformin

Project description:Trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) causes dramatic reductions in white adipose tissue in mice but has had limited effectiveness in humans. Determination of the signaling pathways involved may lead to better regulation of adiposity. T10c12 CLA was found to activate AMP-activating protein kinase (AMPK), a central regulator of cell metabolism. Compound C, a potent inhibitor of AMPK, prevents many of the typical responses to treatments with t10c12 CLA including the integrated stress response (ISR), the inflammatory response, the reduction in key lipogenic transcription factors, and delipidation. Treatment of adipocytes or mice with t10c12 CLA in conjunction with AMPK activator metformin results in more delipidation than treatment with the individual chemicals. Additionally, the combination showed a reduced inflammatory response relative to a t10c12 CLA treatment alone. The combination of t10c12 CLA and metformin, widely used to treat insulin resistance and Type II diabetes, has potential as a treatment for reducing adiposity in humans. Keywords: control/treatment Mouse 3T3-L1 RNA for was isolated from control linoleic acid (LA) and treatment (CLA, CLA+metformin, metformin) samples for analysis on microarrays with three biological reps.

2009-11-01 | E-GEOD-14888 | biostudies-arrayexpress

Importance of AMPK in metformin suppression of liver glucose production

Project description:Metformin is now the most widely prescribed oral anti-diabetic agent worldwide, taken by over 150 million people annually. Although metformin has been used clinically to treat type 2 diabetes for over 60 years. Its mechanism of action remains only partially understood and controversial. In particular, this includes whether AMPK plays a role in metformin suppression of liver glucose production. To address this issue, we knocked out the AMPK catalytic alpha1 and alpha 2 subunits in the liver of HFD-fed adult homozygous mice. These mice were treated with a physiological relevent metformin dose (50 mg/kg/day) for 3 weeks. Liver samples were collected.

2019-11-13 | GSE114234 | GEO

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