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: 11.09). 03/2007; 100(3):328-41. DOI: 10.1161/01.RES.0000256090.42690.05
Source: PubMed

ABSTRACT 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.

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    • "The AMP-activated protein kinase (AMPK) system acts as a sensor for cellular energy status that is conserved in all eukaryotic cells (Towler and Hardie, 2007), it also demonstrated that MARK4-null mice displayed a number of striking changes in metabolism such as reduced adiposity, insulin hypersensitivity, and resistance to high-fat diet-induced weight gain, and thus Downloaded by [Jamia Millia Islamia] at 07:44 26 July 2015 MARK4 inhibitors may provide a novel treatment for obesity and its related metabolic complications, including type 2 diabetes (Sun et al., 2012). MARK4 is also appeared to be a crucial factor that stabilizes microtubules in sertoli cells at the ectoplasmic specialization (Tang et al., 2012). "
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    ABSTRACT: MAP/Microtubule affinity-regulating kinase 4 (MARK4) is a member of adenosine monophosphate-activated protein kinases, directly associated with cancer and neurodegenrative diseases. Here, we have cloned, expressed and purified two variants of MARK4 [the kinase domain (MARK4-F2), and kinase domain alongwith 59 N-terminal residues (MARK4-F1)] and compared their stability at varying pH range. Structural and functional changes were observed by incubating both forms of MARK4 in buffers of different pH. We measured the secondary structure of MARK4 using circular diachroism and tertiary structure by measuring intrinsic fluorescence and absorbance properties alongwith the size of proteins by dynamic light scattering. We observed that at extremes of pH (below pH 3.5 and above pH 9.0), MARK4 is quite stable. However, a remarkable aggregate formation was observed at intermediate pH (between pH 3.5 and 9.0). To further validate this results, we have modelled both forms of MARK4 and performed molecular dymanics simulation for 15 ns. The spectroscopic observations are in excellent agreement with the findings of molecular dymanics simulation. We also performed ATPase activity at varying pH and found a signifcant correlation of structure of MARK4 with its enzyme activity. It is interesting to note that both forms of MARK4 is showing a similar pattern of structure changes with reference to pH.
    Journal of biomolecular Structure & Dynamics 07/2015; 24(1). DOI:10.1080/07391102.2015.1074942 · 2.98 Impact Factor
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    • "The insulin signalling pathway is activated under conditions of nutrient availability, whereas the AMPK pathway is activated when cells are starved. GLUT4 translocation requires either the insulin-dependent PI3K/AKT activation signalling pathway to form glycogen storages or the insulin-independent AMPK activation pathway in skeletal muscle to catabolise glucose as an energy source (Towler & Hardie, 2007). In this study, the activation of InsR and AKT could be the direct evidence to demonstrate the specific effects of tetracosanol only on the insulin-dependent pathway. "
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    ABSTRACT: In this study, we investigated whether tetracosanol, an aliphatic alcohol isolated from Saccharum sinense, enhances insulin receptor kinase activity to exhibit an insulin synergistic effect in vitro and in vivo. The insulin plus tetracosanol enhanced insulin receptor kinase showed that AKT activity was down-regulated by S961 in differentiated L6 myotubes. Meanwhile, insulin plus tetracosanol restored the ability of glucose transporter translocation and glucose uptake in differentiated myotubes with S961-induced insulin resistance in vitro. The modification of carbon chain lengths and the hydroxyl group of tetracosanol showed that it served as a critical chemical structure for the glucostasis effect in vivo. This study provides new evidence to show that tetracosanol can improve glycaemic control via insulin receptor kinase activity induced and leads to the enhancement of glucose transporter translocation to improve glucose uptake. The hydroxyl group of tetracosanol plays a critical role for insulin receptor kinase activity.
    Journal of Functional Foods 04/2015; 14. DOI:10.1016/j.jff.2015.01.033 · 4.48 Impact Factor
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    • "In vitro study of epigallocatechin gallate (EGCG) revealed that it could trigger AMP-activated protein kinase pathway (AMPK) for inhibiting the expression of enzymes of gluconeogenesis (Collins et al., 2007). AMPactivated protein kinase, an energy sensory and regulatory protein, plays a critical role in the metabolism, the efficacy of the new treatment for metabolic syndrome, obesity, postprandial hyperglycemia, and a foremost objective for anti-diabetic drugs like metformin lies in the activation of this pathway (Towler & Hardie, 2007; Zhou et al., 2001). Ferulic acid, a derivative of hydroxycinnamic acid, efficiently contains glycemic index of blood by increased glucokinase activity, glycogen production by liver, and increased plasma insulin level (Jung et al., 2007). "
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    ABSTRACT: Context: Polyphenol-rich marine macroalgae are gaining dietary importance due to their influence over diabetes mellitus and the role as a vital source of high-value nutraceuticals. Their assorted beneficial effects on human health include competitive inhibition of digestive enzymes, varying the activity of hepatic glucose-metabolizing enzymes, lowering the plasma glucose levels, and lipid peroxidation, delaying the aging process. Objective: In this paper, we review the health beneficial effects of polyphenols and phlorotannins from brown seaweeds with special emphasis on their inhibitory effects on carbohydrate-metabolizing enzymes. Methods: A survey of literature from databases such as Sciencedirect, Scopus, Pubmed, Springerlink, and Google Scholar from the year 1973 to 2013 was done to bring together the information relating to drug discovery from brown seaweeds as a source for diabetes treatment. Results: Over the past two decades, 20 different bioactive polyphenols/phlorotannins have been isolated and studied from 10 different brown algae. Discussion of the positive effect on the inhibition of enzymes metabolizing carbohydrates in both in vitro and in vivo experiments are included. Conclusion: Despite the recent advancements in isolating bioactive compounds from seaweeds with potential health benefit or pharmaceutical behavior, studies on the polyphenol effectiveness on glucose homeostasis in human beings are very few in response to their functional characterization. Added research in this area is required to confirm the close connection of polyphenol rich seaweed-based diet consumption with glucose homeostasis and the exciting possibility of prescribing polyphenols to treat the diabetes pandemic.
    Pharmaceutical Biology 01/2015; 53(8). DOI:10.3109/13880209.2014.959615 · 1.34 Impact Factor
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Mhairi Towler