5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-Monophosphate (AICAR), a Highly Conserved Purine Intermediate with Multiple Effects

Daignan‐Fornier, Bertrand; Pinson, Benoı̂t

doi:10.3390/metabo2020292

Cited by 50 publications

(55 citation statements)

References 57 publications

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“…AICAR is taken up by the cell, where it acts as an AMP mimetic, thus potentially affecting multiple proteins regulated by AMP. Within recent years, an increased number of AMPK-independent effects of AICAR have been described together with reports identifying AICAR as a modulator of enzymes such as glycogen phosphorylase, glucokinase, and phosphofructokinase (31). However, because AICAR did not increase insulin sensitivity in muscle from AMPK KD or mdKO mice, any possible AMPK-independent effect of AICAR does not seem to account for changes in glucose uptake in response to insulin.…”

Section: Tbc1d4 Signalingmentioning

confidence: 99%

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

et al. 2014

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An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve an increased cell surface abundance of GLUT4. While increased proximal insulin signaling does not seem to mediate this effect, elevated phosphorylation of TBC1D4, a downstream target of both insulin (Akt) and exercise (AMPK) signaling, appears to play a role. The main purpose of this study was to determine whether AMPK activation increases skeletal muscle insulin sensitivity. We found that prior AICAR stimulation of wild-type mouse muscle increases insulin sensitivity to stimulate glucose uptake. However, this was not observed in mice with reduced or ablated AMPK activity in skeletal muscle. Furthermore, prior AICAR stimulation enhanced insulin-stimulated phosphorylation of TBC1D4 at Thr 649 and Ser 711 in wild-type muscle only. These phosphorylation events were positively correlated with glucose uptake. Our results provide evidence to support that AMPK activation is sufficient to increase skeletal muscle insulin sensitivity. Moreover, TBC1D4 phosphorylation may facilitate the effect of prior AMPK activation to enhance glucose uptake in response to insulin.The effect of insulin on skeletal muscle glucose uptake is increased in the period after a single bout of exercise. This phenomenon is observed in muscle from both humans and rodents (1-6) and may persist for up to 48 h after exercise, depending on carbohydrate availability (7-9). Improved muscle insulin sensitivity postexercise is mediated by one or several local contraction-induced mechanisms (10) involving both enhanced transport and intracellular processing of glucose. This period is characterized by increased GLUT4 protein abundance at the plasma membrane and enhanced glycogen synthase activity (11,12). These changes occur independent of global protein synthesis (13), including both total GLUT4 and glycogen synthase protein content (4,11), and are independent of changes in proximal insulin signaling, including Akt activation (3,4,(13)(14)(15)(16)(17).AMPK is a heterotrimeric complex consisting of catalytic (a1/a2) and regulatory subunits (b1/b2 and g1/g2/g3). Of the 12 heterotrimeric combinations, only 3 and 5 combinations have been found in the skeletal muscle of human and mouse, respectively (18,19). AMPK is activated in response to various stimuli that increase cellular energy stress (e.g., metformin, hypoxia, hyperosmolarity, muscle contraction, and exercise) (20). With energy stress, intracellular concentrations of AMP and ADP accumulate. This activates AMPK allosterically and decreases the ability of upstream phosphatases to dephosphorylate Thr 172 , which further increases AMPK phosphorylation and activity (21). Like exercise, AICAR increases AMPK activity in skeletal muscle (22), which partly mimics the metabolic changes observed during muscle contraction (...

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Section: Tbc1d4 Signalingmentioning

confidence: 99%

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

et al. 2014

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“…AICAR plays a central role in the metabolism and in signal transduction increasing insulin properties, up-regulating mitochondrial enzymes in muscles and decreasing intra-abdominal fat [2][3][4] . It can act as an agonist and antagonist for a number of enzymes crucial for the cell life; among these, AMPKa has a fundamental role in energy homeostasis, being an energy sensor implicated in various 24,25 .…”

Section: Discussionmentioning

confidence: 99%

“…5-Aminoimidazole-4-carboxamide riboside (AICAR) is a potent activator of 5 0 -AMP activated protein kinase (AMPKa), a protein kinase that increases fatty acid oxidation in multiple tissues and also stimulates the uptake and the transport of glucose as well as glycolysis [2][3][4] . At the same time, the activation of AMPKa also results in inhibitory effects on lipogenesis in the liver in an opposite manner compared to those of insulin.…”

Section: Introductionmentioning

confidence: 99%

“…In this context, we have focused on AICAR due to its direct or indirect involvement with a number of important metabolic or signaling events [1][2][3][4] . Unfortunately, AICAR shows some limitations: it has a short half-life in cells; it does not cross efficiently the blood-brain barrier and it is poorly absorbed by the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

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New synthetic AICAR derivatives with enhanced AMPK and ACC activation

Scudiero¹,

Nigro

Monaco

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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5-Aminoimidazole-4-carboxamide riboside (AICAR) has an important role in the regulation of the cellular metabolism showing a broad spectrum of therapeutic activities against different metabolic processes. Due to these proven AICAR properties, we have designed, synthesized and tested the biological activity of two ribose-modified AICAR derivatives, named A3 and A4, in comparison to native AICAR and its 5 0 -phosphorylated counterpart ZMP. Our findings have shown that A3 and A4 derivatives induce the phosphorylation of 5 0 -AMP activated protein kinase a (AMPKa), which leads to the inhibition of acetyl-CoA carboxylase (ACC), and downregulate the activity of the extracellular signal-regulated kinases (ERK1/2). Cytotoxicity tests demonstrated that A3 and A4 do not significantly reduce cell viability up to 24 h. Taken together our results indicate that A3 and A4 have a comparable activity to AICAR and ZMP at 0.5 and 1 mM suggesting their potential use in future pharmacological strategies relating to metabolic diseases.

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“…1A) in the growth medium, is often used as low energy mimetic. AICAR clearly activates AMPK in vitro and in vivo but also shows many effects that are not AMPK-dependent (1,2). Whether these effects are the result of AMP mimicry or not is unknown.…”

mentioning

confidence: 99%

Disruption of Nucleotide Homeostasis by the Antiproliferative Drug 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside Monophosphate (AICAR)

Ceschin¹,

Hürlimann²,

Saint-Marc³

et al. 2015

Journal of Biological Chemistry

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Background: AICAR is a potent anti-proliferative compound, but the basis of its cytotoxicity is poorly understood. Results: AICAR affects NTP homeostasis in a carbon source-dependent way, in both yeast and human cells. Conclusion: AICAR balance with nucleotides triphosphate is critical for its in vivo effects. Significance: AICAR is significantly more cytotoxic on glucose and thus potentially targets cells prone to Warburg effect.

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5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-Monophosphate (AICAR), a Highly Conserved Purine Intermediate with Multiple Effects

Cited by 50 publications

References 57 publications

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

New synthetic AICAR derivatives with enhanced AMPK and ACC activation

Disruption of Nucleotide Homeostasis by the Antiproliferative Drug 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside Monophosphate (AICAR)

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