A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators

Lai, Yu‐Chiang; Kviklyte, Samanta; Vertommen, Didier; Lantier, Louise; Foretz, Marc; Viollet, Benoı̂t; Hallén, Stefan; Rider, Mark H.

doi:10.1042/bj20131673

Cited by 78 publications

(75 citation statements)

References 49 publications

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“…This is an important consideration because previous studies using A769662, the first direct small molecule AMPK activator to be described [3], led to the suggestion that only b1-containing complexes are targets for activation [43]. With the identification of more potent AMPK activators it is now clear that this is not the case [44]. However, the finding that drugs have different binding affinities between b1 and b2 complexes opens up the possibility of designing isoform-selective AMPK activators.…”

Section: Pharmacological Ampk Activatorsmentioning

confidence: 80%

AMPK signalling in health and disease

Carling

2017

Current Opinion in Cell Biology

599

432

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In eukaryotic cells AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance. AMPK responds to changes in intracellular adenine nucleotide levels, being activated by an increase in AMP/ADP relative to ATP. Activation of AMPK increases the rate of catabolic (ATP-generating) pathways and decreases the rate of anabolic (ATP-utilising) pathways. In addition to its role in maintaining intracellular energy balance, AMPK regulates whole body energy metabolism. Given its key role in controlling energy homeostasis, AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases, including type 2 diabetes and, more recently, cancer. Here I review the regulation of AMPK and its potential as a target for therapeutic intervention in human disease. IntroductionThe hydrolysis of ATP to ADP provides the energy for driving virtually all of the processes associated with living cells. Maintaining an adequate supply of energy is an essential requirement for survival [1]. At a single cell level this means keeping ATP, the immediate source of energy, at a relatively high concentration -in the millimolar range in most eukaryotic cells. The concentration of ATP within most eukaryotic cells is kept at a remarkably constant level, despite wide fluctuations in the demand for ATP [2]. In order to achieve this, cells require systems to monitor changes in ATP levels, and to couple these changes to a transponder that leads to functional outputs to restore ATP levels. One such system that has been identified is the AMP-activated protein kinase (AMPK) and orthologues of AMPK are found in virtually all eukaryotes. A major function of AMPK is to monitor changes in the level of ATP and to couple this to phosphorylation of downstream substrates leading to an increase in the rate of ATP-producing pathways and/or a decrease in the rate of ATP-utilising pathways. Dysregulation of energy homeostasis is thought to be an important factor in driving changes in a wide range of human diseases, such as type 2 diabetes, obesity and cancer. The central role of AMPK in maintaining energy homeostasis has made it an attractive target for drugs aimed at preventing and/or treating metabolic diseases, including cancer [3][4][5]. In this review, I will focus on recent developments regarding the regulation of AMPK that directly impact on its therapeutic utility. I will also discuss some potential caveats arising from studies examining the role of AMPK in vivo using mouse models.

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Section: Pharmacological Ampk Activatorsmentioning

confidence: 80%

AMPK signalling in health and disease

Carling

2017

Current Opinion in Cell Biology

599

432

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“…The β-subunit contains a conserved glycogen-binding domain called the carbohydrate-binding module (CBM), forming an interface between the α-and γ-subunits. High glycogen levels, particularly in muscle, antagonize AMPK activation (McBride and Hardie 2009;Lai et al 2014). Interestingly, the CBM can be recognized in the AMPKβ subunit sequences of protists, such as Giardia lamblia.…”

Section: Regulation Of Ampkmentioning

confidence: 97%

Role of AMP-activated protein kinase in metabolic depression in animals

Rider

2015

J Comp Physiol B

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AMP-activated protein kinase (AMPK) is a highly conserved eukaryotic protein serine/threonine kinase that controls cellular and whole body energy homoeostasis. AMPK is activated during energy stress by a rise in AMP:ATP ratio and maintains energy balance by phosphorylating targets to switch on catabolic ATP-generating pathways, while at the same time switching off anabolic ATP-consuming processes. Metabolic depression is a strategy used by many animals to survive environmental stress and has been extensively studied across phylogeny by comparative biochemists and physiologists, but the role of AMPK has only recently been addressed. This review first deals with the evolution of AMPK in eukaryotes (excluding plants and fungi) and its regulation. Changes in adenine nucleotides and AMPK activation are described in animals during environmental energy stress, before considering the involvement of AMPK in controlling β-oxidation, fatty acid synthesis, triacylglycerol mobilization and protein synthesis. Lastly, strategies are presented to validate the role of AMPK in mediating metabolic depression by phosphorylating downstream targets.

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“…At a much higher concentration (2 mM), A769662 stimulated glucose uptake; however, it was mediated through an AMPK-independent/phosphoinositide 3-kinase-dependent mechanism due to unknown off-target effect(s) (43). Another small-molecule AMPK activator, 991 [also known as ex229 (22)], has recently been described. Structural studies have shown that 991 binds to a site formed between the small lobe of the α-subunit kinase domain and the β-subunit carbohydrate-binding module (4, 46), which is also the binding site for A769662, termed the allosteric drug and metabolite-binding site (ADaM) (23).…”

mentioning

confidence: 99%

“…Structural studies have shown that 991 binds to a site formed between the small lobe of the α-subunit kinase domain and the β-subunit carbohydrate-binding module (4, 46), which is also the binding site for A769662, termed the allosteric drug and metabolite-binding site (ADaM) (23). 991 is 5- to 10-fold more potent than A769662 in cell-free assays (46) and has been shown to stimulate AMPK activity of both β1- and β2-containing complexes and to increase glucose transport in isolated mouse skeletal muscle ex vivo (22). …”

mentioning

confidence: 99%

Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle

Bultot

Jensen

Lai

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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AMP-activated protein kinase (AMPK) plays diverse roles and coordinates complex metabolic pathways for maintenance of energy homeostasis. This could be explained by the fact that AMPK exists as multiple heterotrimer complexes comprising a catalytic α-subunit (α1 and α2) and regulatory β (β1 and β2)- and γ (γ1, γ2, γ3)-subunits, which are uniquely distributed across different cell types. There has been keen interest in developing specific and isoform-selective AMPK-activating drugs for therapeutic use and also as research tools. Moreover, establishing ways of enhancing cellular AMPK activity would be beneficial for both purposes. Here, we investigated if a recently described potent AMPK activator called 991, in combination with the commonly used activator 5-aminoimidazole-4-carboxamide riboside or contraction, further enhances AMPK activity and glucose transport in mouse skeletal muscle ex vivo. Given that the γ3-subunit is exclusively expressed in skeletal muscle and has been implicated in contraction-induced glucose transport, we measured the activity of AMPKγ3 as well as ubiquitously expressed γ1-containing complexes. We initially validated the specificity of the antibodies for the assessment of isoform-specific AMPK activity using AMPK-deficient mouse models. We observed that a low dose of 991 (5 μM) stimulated a modest or negligible activity of both γ1- and γ3-containing AMPK complexes. Strikingly, dual treatment with 991 and 5-aminoimidazole-4-carboxamide riboside or 991 and contraction profoundly enhanced AMPKγ1/γ3 complex activation and glucose transport compared with any of the single treatments. The study demonstrates the utility of a dual activator approach to achieve a greater activation of AMPK and downstream physiological responses in various cell types, including skeletal muscle.

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A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators

Cited by 78 publications

References 49 publications

AMPK signalling in health and disease

AMPK signalling in health and disease

Role of AMP-activated protein kinase in metabolic depression in animals

Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle

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