Metformin: An Inhibitor of mTORC1 Signaling - Abstract
Recent progress in molecular medicine has identified the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) as the central regulator of protein and lipid synthesis, cell growth, proliferation, energy metabolism and autophagy. Age-related diseases of Western civilization such as obesity, diabetes mellitus, neurodegenerative diseases, and cancer are associated with enhanced mTORC1 signaling. According to the current opinion, metformin’s primary mode of action is the alteration of cellular energy metabolism stimulating 5-AMP-Activated Protein Kinase (AMPK). However, the notion that AMPK primarily mediates metformin´s anti-hyperglycemic action has recently been challenged, thrusting AMPK-independent effects into the focus of interest. We provide a new viewpoint on metformin´s mode of action as an inhibitor of mTORC1. Metformin´s insulin-lowering and AMPK-activating effects decrease RHEB-mediated stimulation of mTORC1. Independent of AMPK metformin inhibits mTORC1 in a RAG GTPase-dependent manner. Thus, metformin interferes with the two major pathways required for mTORC1 activation: 1) energy- and cell stress-mediated activation of AMPK attenuating the activity of the GTPase RHEB and 2) suppression of amino acid signaling down-regulating the activity of lysosomal RAG GTPases. Both RHEB- and RAG GTPase activation, which are required for mTORC1 activation at the lysosomal membrane, are thus suppressed by metformin. Metformin-induced suppression of mTORC1 subsequently decreases S6K1 activity and S6K1-mediated insulin resistance as well as AKT-FoxO1-mediated hepatic gluconeogenesis. Metformin represents an ideal, save and cheap drug targeting the pathogenesis of mTORC1-driven anabolic and hyperproliferative diseases of civilization.