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

ABSTRACT: 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.

SUBMITTER: Van Nostrand JL

PROVIDER: S-EPMC7528705 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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

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

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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

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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

| PRJNA659995 | ENA

The AMPK agonist AICAR, but not metformin, prevents inflammation-associated cachectic muscle wasting

Project description:Activation of AMPK has been associated with pro-atrophic signaling in muscle. However, AMPK also has anti-inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory-driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα-induced atrophy, while the mitochondrial inhibitor, metformin, does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin. In contrast, AICAR partially restored metabolic function. The effects of AICAR were prevented by the AMPK inhibitor Compound C and were reproduced with A-769662, a specific AMPK activator. AICAR and A-769662 co-treatment was found to be synergistic, suggesting that the anti-cachectic effects of these drugs are mediated through AMPK activation. AICAR spared muscle mass in mouse models of cancer and LPS induced atrophy. Together, our findings suggest a dual function for AMPK during inflammation-driven atrophy, wherein it can play a protective role when activated exogenously early in disease progression, but may contribute to anabolic suppression and atrophy when activated later through mitochondrial dysfunction and subsequent metabolic stress.

| S-SCDT-EMM-2017-08307 | biostudies-other

AMPK phosphorylation of raptor mediates a metabolic checkpoint.

Project description:AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.

| S-EPMC2674027 | biostudies-literature

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