Interaction between the AMP-Activated Protein Kinase and mTOR Signaling Pathways
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Medicine & Science in Sports & Exercise
(Impact Factor: 3.98).
12/2006; 38(11):1958-64. DOI: 10.1249/01.mss.0000233796.16411.13
The AMP-activated protein kinase (AMPK) has been referred to as an "energy sensor" because it binds to and is regulated by both AMP and ATP. The binding of AMP to AMPK allows it to be phosphorylated by upstream kinases, resulting in its activation. In contrast, the binding of ATP prevents its activation. AMPK regulates a multitude of metabolic processes that cumulatively function to maintain cellular energy homeostasis through repression of a number of energy-consuming processes with simultaneous enhancement of energy-producing processes. One downstream AMPK target that has been recently identified is the mammalian target of rapamycin (mTOR), a positive effector of cell growth and division. The focus of the present review is to briefly summarize current knowledge concerning the regulation of mTOR signaling by AMPK.
Available from: Vincenzo Borelli
- "Previous studies suggest that metformin suppresses mTOR, a central regulator of protein synthesis and cell growth . We found an increase in gene expression of mTOR in PBMCs of metformin-treated participants, which was not parallelled by an increase in mTOR protein. "
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ABSTRACT: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects.
In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo.
In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. CLINICALTRIALS.
NCT01765946 - January 2013.
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Available from: Chad R Hancock
- "The regulation of SREBP-1c by AMPK is thought to be dependent upon inhibition of mammalian target of rapamycin (mTOR) and transcriptional activity of liver X receptor (LXR) and SREBP-1c [4,35,64]. SREBP-1c is significantly decreased by inhibitors of mTOR such as rapamycin. . "
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High fat feeding increases hepatic fat accumulation and is associated with hepatic insulin resistance. AMP Activated Protein Kinase (AMPK) is thought to inhibit lipid synthesis by the acute inhibition of glycerol-3-phosphate acyltransferase (GPAT) activity and transcriptional regulation via sterol regulatory element binding protein-1c (SREBP-1c).
The purpose of this study was to determine if chronic activation of AMPK prevented an increase in GPAT1 activity in rats fed a high fat diet. Rats were fed a control (C), or a high fat (HF) diet (60% fat) for 6 weeks and injected with saline or a daily aminoimidazole carboxamide ribnucleotide (AICAR) dose of 0.5 mg/g body weight.
Chronic AMPK activation by AICAR injections resulted in a significant reduction in hepatic triglyceride accumulation in both the C and HF fed animals (C, 5.5±0.7; C+AICAR, 2.7 ±0.3; HF, 21.8±3.3; and HF+AICAR, 8.0±1.8 mg/g liver). HF feeding caused an increase in total GPAT and GPAT1 activity, which was not affected by chronic AMPK activation (GPAT1 activity vs. C, C+AICAR, 92±19%; HF, 186±43%; HF+AICAR, 234±62%). Markers of oxidative capacity, including citrate synthase activity and cytochrome c abundance, were not affected by chronic AICAR treatment. Interestingly, HF feeding caused a significant increase in long chain acyl-CoA dehydrogenase or LCAD (up 66% from C), a marker of fatty acid oxidation capacity.
These results suggest that chronic AMPK activation limits hepatic triglyceride accumulation independent of a reduction in total GPAT1 activity.
Available from: Stuart Andrew Shaw Craig
- "Endurance training adaptations which signal through the adenosine monophosphate-activated kinase (AMPK)/peroxisome-proliferator-activated receptor c coactivator 1a (PGC-1a) pathway (Kimball 2006) inhibit the mTOR pathway and decrease protein synthesis (Coffey et al. 2006). Cortisol and other glucocorticoids inhibit p70 S6k phosphorylation, a downstream event in mTOR signaling (Shah et al. 2000a, b, 2002). "
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ABSTRACT: Our aim was to examine the effect of betaine supplementation on selected circulating hormonal measures and Akt muscle signaling proteins after an acute exercise session. Twelve trained men (age 19.7 ± 1.23 years) underwent 2 weeks of supplementation with either betaine (B) (1.25 g BID) or placebo (P). Following a 2-week washout period, subjects underwent supplementation with the other treatment (B or P). Before and after each 2-week period, subjects performed an acute exercise session (AES). Circulating GH, IGF-1, cortisol, and insulin were measured. Vastus lateralis samples were analyzed for signaling proteins (Akt, p70 S6k, AMPK). B (vs. P) supplementation approached a significant increase in GH (mean ± SD (Area under the curve, AUC), B: 40.72 ± 6.14, P: 38.28 ± 5.54, p = 0.060) and significantly increased IGF-1 (mean ± SD (AUC), B: 106.19 ± 13.45, P: 95.10 ± 14.23, p = 0.010), but significantly decreased cortisol (mean ± SD (AUC), B: 1,079.18 ± 110.02, P: 1,228.53 ± 130.32, p = 0.007). There was no difference in insulin (AUC). B increased resting Total muscle Akt (p = 0.003). B potentiated phosphorylation (relative to P) of Akt (Ser(473)) and p70 S6 k (Thr(389)) (p = 0.016 and p = 0.005, respectively). Phosphorylation of AMPK (Thr(172)) decreased during both treatments (both p = 0.001). Betaine (vs. placebo) supplementation enhanced both the anabolic endocrine profile and the corresponding anabolic signaling environment, suggesting increased protein synthesis.
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