AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling

Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
Circulation Research (Impact Factor: 11.02). 03/2007; 100(3):328-41. DOI: 10.1161/01.RES.0000256090.42690.05
Source: PubMed


The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.

Full-text preview

Available from:
  • Source
    • "AMPK, as the name suggests is AMP activated protein kinase. Under conditions of stress that either lead to an increase in ATP consumption or a decrease in ATP production, there is an increase in the cellular AMP:ATP ratio (Towler and Hardie, 2007). Binding of AMP to the γ subunit of AMPK results in a conformational change which activate AMPK by: 1) Increasing the phosphorylation of Thr 172 by upstream kinases, 2) Decreasing the dephosphorylation by phosphotases, 3) Allosterically increasing the AMPK activity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NFAT-133 is an aromatic compound with cinammyl alcohol moiety, isolated from streptomycetes strain PM0324667. We have earlier reported that NFAT-133 increases insulin stimulated glucose uptake in L6 myotubes using a PPARγ independent mechanism and reduces plasma or blood glucose levels in diabetic mice. Here we investigated the effects of NFAT-133 on cellular signaling pathways leading to glucose uptake in L6 myotubes. Our studies demonstrate that NFAT-133 increases glucose uptake in a dose- and time-dependent manner independent of the effects of insulin. Treatment with Akti-1/2, wortmannin and increasing concentrations of insulin had no effect on NFAT-133 mediated glucose uptake. NFAT-133 induced glucose uptake is completely mitigated by Compound C, an AMPK inhibitor. Further, the kinases upstream of AMPK activation namely; LKB-1 and CAMKKβ are not involved in NFAT-133 mediated AMPK activation nor does the compound NFAT-133 have any effect on AMPK enzyme activity. Further analysis confirmed that NFAT-133 indirectly activates AMPK by reducing the mitochondrial membrane potential and increasing the ratio of AMP:ATP.
    European journal of pharmacology 11/2015; DOI:10.1016/j.ejphar.2015.11.006 · 2.53 Impact Factor
  • Source
    • "Therefore, there is an urgent need for alternative hepatoprotective agents. Adenosine monophosphate-activated protein kinase (AMPK) is a serine-threonine kinase heterotrimer that consists of a catalytic α subunit and regulatory β, and γ subunits (Hardie and Sakamoto, 2006; Towler and Hardie, 2007). In mammals, AMPK is activated by metabolic stress such as hypoglycemia, hypoxia, and exercise that increase intracellular AMP, as well as by other allosteric effectors (Hardie and Sakamoto, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The1hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAPinduced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAPmediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAPmediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.
    Moleculer Cells 10/2015; DOI:10.14348/molcells.2015.0072 · 2.09 Impact Factor
  • Source
    • "The functional AMP-activated protein kinase (AMPK) is a heterotrimer consisting of a catalytic alpha (α), a regulatory gamma (γ) and a scaffolding beta (β) subunit and is activated by low cellular energy status (Salminen et al. 2012). AMPK activation orchestrates many biochemical events including glucose uptake, glycolysis, oxidation of free fatty acids (FFAs) and mitochondrial biogenesis (Towler et al. 2007). These processes significantly contribute to raise ATP levels and restore myocardial contractile efficiency and vascular responses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Age is one of the major risk factors associated with cardiovascular disease (CVD). About one fifth of the world population will be aged 65 or older by 2030 with an exponential increase in CVD prevalence. It is well established that environmental factors (overnutrition, smoking, pollution, sedentary lifestyles) may lead to premature defects in mitochondrial functionality, insulin signalling, endothelial homeostasis and redox balance fostering early senescent features. Over the last few years, molecular investigations unveiled common signalling networks which may link the aging process with deterioration of cardiovascular homeostasis and metabolic disturbances, namely insulin resistance. These different processes seem to be highly interconnected and their interplay may favour adverse vascular and cardiac phenotypes responsible for myocardial infarction, stroke and heart failure. In the present review, we carefully describe novel molecular cues underpinning aging, metabolism and CVD. In particular, we describe a dynamic interplay between emerging pathways such as FOXOs, AMPK, SIRT1, p66(Shc) , JunD and NF-kB. Such an overview will provide the background for attractive molecular targets to prevent age-driven pathology in the vasculature and the heart. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 09/2015; DOI:10.1113/JP270538 · 5.04 Impact Factor
Show more