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

Authors

Jeanine L Van Nostrand
Kristina Hellberg
En-Ching Luo
Eric L Van Nostrand
Alina Dayn
Jingting Yu
Maxim N Shokhirev
Yelena Dayn
Gene W Yeo
Reuben J Shaw

Publication Date

10-1-2020

Journal

Genes Development

DOI

10.1101/gad.339895.120

PMID

32912901

PMCID

PMC7528705

PubMedCentral® Posted Date

10-1-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

AMP-Activated Protein Kinases, Animals, Diabetes Mellitus, Type 2, Disease Models, Animal, Gene Expression Regulation, Gene Knock-In Techniques, Genotype, Hypoglycemic Agents, Inflammation, Mechanistic Target of Rapamycin Complex 1, Metabolism, Metformin, Mice, Phosphorylation, Regulatory-Associated Protein of mTOR, Signal Transduction, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 2 Protein, AMPK, mTOR, RAPTOR, TSC2, metformin, STAT3

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

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