AMP-activated protein kinase
|[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase|
AMP-activated protein kinase
|PDB structures||RCSB PDB PDBe PDBsum|
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells.
- 1 Structure
- 2 Function
- 3 Activation
- 4 Regulation by adipocytokines
- 5 Clinical significance
- 6 Controversy over role in adaption to exercise/training
- 7 See also
- 8 References
- 9 External links
The heterotrimeric protein AMPK is formed by α, β, and γ subunits. Each of these three subunits takes on a specific role in both the stability and activity of AMPK. Specifically, the γ subunit includes four particular Cystathionine beta synthase (CBS) domains giving AMPK its ability to sensitively detect shifts in the AMP:ATP ratio. The four CBS domains create two binding sites for AMP commonly referred to as Bateman domains. Binding of one AMP to a Bateman domain cooperatively increases the binding affinity of the second AMP to the other Bateman domain.[not in citation given] As AMP binds both Bateman domains the γ subunit undergoes a conformational change which exposes the catalytic domain found on the α subunit. It is in this catalytic domain where AMPK becomes activated when phosphorylation takes place at threonine-172 by an upstream AMPK kinase (AMPKK). The α, β, and γ subunits can also be found in different isoforms: the γ subunit can exist as either the γ1, γ2 or γ3 isoform; the β subunit can exist as either the β1 or β2 isoform; and the α subunit can exist as either the α1 or α2 isoform. Although the most common isoforms expressed in most cells are the α1, β1, and γ1 isoforms, it has been demonstrated that the α2, β2, γ2, and γ3 isoforms are also expressed in cardiac and skeletal muscle.
The following human genes encode AMPK subunits:
AMPK acts as a metabolic master switch regulating several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids and the biogenesis of glucose transporter 4 (GLUT4) and mitochondria. The energy-sensing capability of AMPK can be attributed to its ability to detect and react to fluctuations in the AMP:ATP ratio that take place during rest and exercise (muscle stimulation). During muscle stimulation, AMP increases while ATP decreases, which changes AMPK into a good substrate for activation via an upstream kinase complex, AMPKK, or better, where binding of AMP renders activated AMPK that is phosphorylated at Thr-172 a worse substrate for protein phosphatase 2Calpha. AMPKK is a complex of three proteins, STE-related adaptor (STRAD), mouse protein 25 (MO25), and LKB1 (a serine/threonine kinase). During a bout of exercise, AMPK activity increases while the muscle cell experiences metabolic stress brought about by an extreme cellular demand for ATP. Upon activation, AMPK increases cellular energy levels by inhibiting anabolic energy consuming pathways (fatty acid synthesis, protein synthesis, etc.) and stimulating energy producing, catabolic pathways (fatty acid oxidation, glucose transport, etc.).
A recent JBC paper on mice at Johns Hopkins has shown that when the activity of brain AMPK was pharmacologically inhibited, the mice ate less and lost weight. When AMPK activity was pharmacologically raised (AICAR see below) the mice ate more and gained weight. Research in hibernators has also shown that activation of AMPK induces arousal from hibernation and stimulates food intake. Research in Britain has shown that the appetite-stimulating hormone ghrelin also affects AMPK levels. The antidiabetic drug metformin (Glucophage) acts by stimulating AMPK, leading to reduced glucose production in the liver and reduced insulin resistance in the muscle. (Metformin usually causes weight loss and reduced appetite, not weight gain and increased appetite, which is opposite of what might be expected given the Johns Hopkins mouse study results. )
Triggering the activation of AMPK can be carried out provided that two conditions are met. First, the γ subunit of AMPK must undergo a conformational change so as to expose the active site (Thr-172) on the α subunit. The conformational change of the γ subunit of AMPK can be accomplished under increased concentrations of AMP. Increased concentrations of AMP will give rise to the conformational change on the γ subunit of AMPK as two AMP bind the two Bateman domains located on that subunit. It is this conformational change brought about by increased concentrations of AMP that exposes the active site (Thr-172) on the α subunit. This critical role of AMP is further substantiated in experiments that demonstrate AMPK activation via an AMP analogue 5-amino-4-imidazolecarboxamide ribotide (ZMP) which is derived from 5-amino-4-imidazolecarboxamide riboside (AICAR). The second condition that must be met is the phosphorylation and consequent activation of AMPK on its activating loop at Thr-172 of the α subunit brought about by an upstream kinase (AMPKK). The complex formed between LKB1 (STK 11), mouse protein 25 (MO25), and the pseudokinase STE-related adaptor protein (STRAD) has of late been identified as the major upstream kinase responsible for phosphorylation of AMPK on its activating loop at Thr-172. Although AMPK must be phosphorylated by the LKB1/MO25/STRAD complex, it can also be regulated by allosteric modulators which directly increase general AMPK activity and modify AMPK to make it a better substrate for AMPKK and a worse substrate for phosphatases. It has recently been found that 3-phosphoglycerate (glycolysis intermediate) acts to further pronounce AMPK activation via AMPKK.
Muscle contraction is the main method carried out by the body that can provide the conditions mentioned above needed for AMPK activation. As muscles contract, ATP is hydrolyzed, forming ADP. ADP then helps to replenish cellular ATP by donating a phosphate group to another ADP, forming an ATP and an AMP. As more AMP is produced during muscle contraction, the AMP:ATP ratio dramatically increases, leading to the allosteric activation of AMPK. This fact is further authenticated with studies, such as those cited above, that used electrical stimuli as a means to contract muscle to facilitate AMPK activation. For over a decade it has been known that calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) can phosphorylate and thereby activate AMPK, but it was not the main AMPKK in liver. Richter et al. found that CaMKK inhibitors strongly inhibited AMPK phosphorylation in mouse soleus and EDL muscles after 2 minutes of contraction, but much less as time of contraction increased. CaMKK inhibitors had no effect on 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) phosphorylation and activation of AMPK. AICAR is taken into the cell and converted to ZMP, an AMP analog that has been shown to activate AMPK. Recent LKB1 knockout studies have shown that without LKB1, electrical and AICAR stimulation of muscle results in very little phosphorylation of AMPK and of ACC, providing evidence that LKB1-STRAD-MO25 is the major AMPKK in muscle.
Regulation by adipocytokines
Adipokines, also known as adipocytokines, are secreted by adipose tissue to take on several different but important physiological roles in the body including the regulation of appetite, metabolism, fatty acid catabolism, coagulation and systemic inflammation, for example. Collectively, the adipokines are cytokines (cell-to-cell signaling proteins) which, when secreted, act on other cells, usually resulting in a biochemical and metabolic response. Two particular adipokines, adiponectin and leptin, have even been demonstrated to regulate AMPK.
Among the metabolic roles of leptin, one of its main functions in skeletal muscle is the upregulation of fatty acid oxidation. A study revealed that leptin is able to do this by way of the AMPK signaling pathway. A similar study showed that much like leptin, adiponectin also stimulates the oxidation of fatty acids via the AMPK pathway, and that it also stimulates the uptake of glucose in skeletal muscle. As yet, the metabolic roles of leptin and adiponectin pertaining to biochemical adaptations to long-term endurance training remain unclear. Certainly future studies will involve an investigation of leptin and adiponectin activities and their respective relationships with the AMPK signaling pathway immediately following a high-intensity endurance training protocol.
Many biochemical adaptations of skeletal muscle that take place during a single bout of exercise or an extended duration of training, such as increased mitochondrial biogenesis and capacity, increased muscle glycogen, and an increase in enzymes which specialize in glucose uptake in cells such as GLUT4 and hexokinase II  are thought to be mediated in part by AMPK when it is activated. Additionally, recent discoveries can conceivably suggest a direct AMPK role in increasing blood supply to exercised/trained muscle cells by stimulating and stabilizing both vasculogenesis and angiogenesis. Taken together, these adaptations most likely transpire as a result of both temporary and maintained increases in AMPK activity brought about by increases in the AMP:ATP ratio during single bouts of exercise and long-term training.
During a single acute exercise bout, AMPK allows the contracting muscle cells to adapt to the energy challenges by increasing expression of hexokinase II, translocation of GLUT4 to the plasma membrane, for glucose uptake, and by stimulating glycolysis. If bouts of exercise continue through a long-term training regimen, AMPK and other signals will facilitate contracting muscle adaptations by escorting muscle cell activity to a metabolic transition resulting in an oxidative dependent approach to energy metabolism as opposed to a glycolytic approach. AMPK accomplishes this transition to the oxidative mode of metabolism by upregulating and activating oxidative enzymes such as GLUT4, hexokinase II, PPARalpha, PGC-1, UCP3, cytochrome C and TFAM.
AMPK activity increases with exercise and the LKB1/MO25/STRAD complex is considered to be the major upstream AMPKK of the 5’-AMP-activated protein kinase phosphorylating the α subunit of AMPK at Thr-172. This fact is puzzling considering that although AMPK protein abundance has been shown to increase in skeletal tissue with endurance training, its level of activity has been shown to decrease with endurance training in both trained and untrained tissue. Currently, the activity of AMPK immediately following a 2-hr bout of exercise of an endurance trained rat is unclear. It is possible that there exists a direct link between the observed decrease in AMPK activity in endurance trained skeletal muscle and the apparent decrease in the AMPK response to exercise with endurance training.
Controversy regarding AMPK's role in exercise training adaptation
Although AMPKalpha2 activation has been thought to be important for mitochondrial adaptations to exercise training, a recent study investigating the response to exercise training in AMPKa2 knockout mice opposes this idea. Their study compared the response to exercise training of several proteins and enzymes in wild type and AMPKalpha2 knockout mice. And even though the knockout mice had lower basal markers of mitochondrial density (COX-1, CS, and HAD), these markers increased similarly to the wild type mice after exercise training. These findings are supported by another study also showing no difference in mitochondrial adaptations to exercise training between wild type and knockout mice.
Maximum life span
The C. elegans homologue of AMPK, aak-2, has been shown by Michael Ristow and colleagues to be required for extension of life span in states of glucose restriction mediating a process named mitohormesis.
One of the effects of exercise is an increase in fatty acid metabolism, which provides more energy for the cell. One of the key pathways in AMPK’s regulation of fatty acid oxidation is the phosphorylation and inactivation of acetyl-CoA carboxylase. Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT-1). CPT-1 transports fatty acids into the mitochondria for oxidation. Inactivation of ACC, therefore, results in increased fatty acid transport and subsequent oxidation. It is also thought that the decrease in malonyl-CoA occurs as a result of malonyl-CoA decarboxylase (MCD), which may be regulated by AMPK. MCD is an antagonist to ACC, decarboxylating malonyl-CoA to acetyl-CoA, resulting in decreased malonyl-CoA and increased CPT-1 and fatty acid oxidation. AMPK also plays an important role in lipid metabolism in the liver. It has long been known that hepatic ACC has been regulated in the liver by phosphorylation. AMPK also phosphorylates and inactivates 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol synthesis. HMGR converts 3-hydroxy-3-methylglutaryl-CoA, which is made from acetyl-CoA, into mevalonic acid, which then travels down several more metabolic steps to become cholesterol. AMPK, therefore, helps regulate fatty acid oxidation and cholesterol synthesis.
Insulin is a hormone which helps regulate glucose levels in the body. When blood glucose is high, insulin is released from the Islets of Langerhans. Insulin, among other things, will then facilitate the uptake of glucose into cells via increased expression and translocation of glucose transporter GLUT-4. Under conditions of exercise, however, blood sugar levels are not necessarily high, and insulin is not necessarily activated, yet muscles are still able to bring in glucose. AMPK seems to be responsible in part for this exercise-induced glucose uptake. Goodyear et al. observed that with exercise, the concentration of GLUT-4 was increased in the plasma membrane, but decreased in the microsomal membranes, suggesting that exercise facilitates the translocation of vesicular GLUT-4 to the plasma membrane. While acute exercise increases GLUT-4 translocation, endurance training will increase the total amount of GLUT-4 protein available. It has been shown that both electrical contraction and AICAR treatment increase AMPK activation, glucose uptake, and GLUT-4 translocation in perfused rat hindlimb muscle, linking exercise-induced glucose uptake to AMPK. Chronic AICAR injections, simulating some of the effects of endurance training, also increase the total amount of GLUT-4 protein in the muscle cell.
Two proteins are essential for the regulation of GLUT-4 expression at a transcriptional level – myocyte enhancer factor 2 (MEF2) and GLUT4 enhancer factor (GEF). Mutations in the DNA binding regions for either of these proteins results in ablation of transgene GLUT-4 expression. These results prompted a study in 2005 which showed that AMPK directly phosphorylates GEF, but it doesn’t seem to directly activate MEF2. AICAR treatment has been shown, however, to increase transport of both proteins into the nucleus, as well as increase the binding of both to the GLUT-4 promoter region.
There is another protein involved in carbohydrate metabolism that is worthy of mention along with GLUT-4. The enzyme hexokinase phosphorylates a six-carbon sugar, most notably glucose, which is the first step in glycolysis. When glucose is transported into the cell it is phosphorylated by hexokinase. This phosphorylation keeps glucose from leaving the cell, and by changing the structure of glucose through phosphorylation, it decreases the concentration of glucose molecules, allowing a gradient for more glucose to be transported into the cell. Hexokinase II transcription is increased in both red and white skeletal muscle upon treatment with AICAR. With chronic injections of AICAR, total protein content of hexokinase II increases in rat skeletal muscle.
Mitochondrial enzymes, such as cytochrome c, succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, and citrate synthase, increase in expression and activity in response to exercise. AICAR stimulation of AMPK increases cytochrome c and δ-aminolevulinate synthase (ALAS), a rate-limiting enzyme involved in the production of heme. Malate dehydrogenase and succinate dehydrogenase also increase, as well as citrate synthase activity, in rats treated with AICAR injections. Conversely, in LKB1 knockout mice, there are decreases in cytochrome c and citrate synthase activity, even if the mice are "trained" by voluntary exercise.
To do this, it enhances the activity of transcription factors like nuclear respiratory factor 1 (NRF-1), myocyte enhancer factor 2 (MEF2), host cell factor (HCF), and others. It also has a positive feedback loop, enhancing its own expression.
Both MEF2 and cAMP response element (CRE) are essential for contraction-induced PGC-1α promoter activity. AMPK is required for increased PGC-1α expression in skeletal muscle in response to creatine depletion. LKB1 knockout mice show a decrease in PGC-1α, as well as mitochondrial proteins.
AMPK and thyroid hormone regulate some similar processes. Knowing these similarities, Winder and Hardie et al. designed an experiment to see if AMPK was influenced by thyroid hormone. They found that all of the subunits of AMPK were increased in skeletal muscle, especially in the soleus and red quadriceps, with thyroid hormone treatment. There was also an increase in phospho-ACC, a marker of AMPK activity.
Controversy over role in adaption to exercise/training
A seemingly paradoxical role of AMPK occurs when we take a closer look at the energy-sensing enzyme in relation to exercise and long-term training. Similar to short-term acute training scale, long-term endurance training studies also reveal increases in oxidative metabolic enzymes and increases in GLUT-4, mitochondrial size and quantity, and an increased dependency on the oxidation of fatty acids; however, Winder et al. reported in 2002 that despite observing these increased oxidative biochemical adaptations to long-term endurance training (similar to those mentioned above), the AMPK response (activation of AMPK with the onset of exercise) to acute bouts of exercise decreased in red quadriceps (RQ) with training (3 – see Fig.1). Conversely, the study did not observe the same results in white quadriceps (WQ) and soleus (SOL) muscles that they did in RQ. The trained rats used for that endurance study ran on treadmills 5 days/wk in two 1-h sessions, morning and afternoon. The rats were also running up to 31m/min (grade 15%). Finally, following training, the rats were sacrificed either at rest or following 10 min. of exercise.
Because the AMPK response to exercise decreases with increased training duration, many questions arise that would challenge the AMPK role with respect to biochemical adaptations to exercise and endurance training. This is due in part to the marked increases in the biogenesis and upregulation of mitochondria, GLUT-4, UCP-3, Hexokinase II and other metabolic and mitochondrial enzymes despite decreases in AMPK activity with training. Questions also arise because skeletal muscle cells which express these decreases in AMPK activity in response to endurance training also seem to be maintaining an oxidative dependent approach to energy metabolism, which is likewise thought to be regulated to some extent by AMPK activity.
If the AMPK response to exercise is responsible in part for biochemical adaptations to training, how then can these adaptations to training be maintained if the AMPK response to exercise is being attenuated with training? It is hypothesized that these adaptive roles to training are maintained by AMPK activity and that the increases in AMPK activity in response to exercise in trained skeletal muscle have not yet been observed due to biochemical adaptations that the training itself stimulated in the muscle tissue to reduce the metabolic need for AMPK activation. In other words, AMPK will not become activated until it is "apparent" that the cell is in need of greater adaptation to exercise. Until energy stores (ATP) are depleted (ATP low + AMP high), AMPK will remain inactivated. Biochemical preparations for a high-intensity energy challenge must be exhausted before AMPK is to be activated in order to mediate further metabolic adaptations to exercise.
- Winder WW, Hardie DG (July 1999). "AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes". Am. J. Physiol. 277 (1 Pt 1): E1–10. PMID 10409121.
- Hallows KR, Alzamora R, Li H, Gong F, Smolak C, Neumann D, Pastor-Soler NM (April 2009). "AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells". Am. J. Physiol., Cell Physiol. 296 (4): C672–81. doi:10.1152/ajpcell.00004.2009. PMC 2670645. PMID 19211918.
- Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE (January 1996). "Mammalian AMP-activated protein kinase subfamily". J. Biol. Chem. 271 (2): 611–4. doi:10.1074/jbc.271.2.611. PMID 8557660.
- Adams J, Chen ZP, Van Denderen BJ, Morton CJ, Parker MW, Witters LA, Stapleton D, Kemp BE (January 2004). "Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site". Protein Sci. 13 (1): 155–65. doi:10.1110/ps.03340004. PMC 2286513. PMID 14691231.
- Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG (November 1996). "Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase". J. Biol. Chem. 271 (44): 27879–87. doi:10.1074/jbc.271.44.27879. PMID 8910387.
- Thornton C, Snowden MA, Carling D (May 1998). "Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle". J. Biol. Chem. 273 (20): 12443–50. doi:10.1074/jbc.273.20.12443. PMID 9575201.
- Cheung PC, Salt IP, Davies SP, Hardie DG, Carling D (March 2000). "Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding". Biochem. J. 346 (3): 659–69. doi:10.1042/0264-6021:3460659. PMC 1220898. PMID 10698692.
- Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT, Martin SR, Carling D, Gamblin SJ. (Sep 2007). "Structural basis for AMP binding to mammalian AMP-activated protein kinase.". Nature 449 (7161): 496–500. doi:10.1038/nature06161. PMID 17851531.
- Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P, Howell SA, Aasland R, Martin SR, Carling D, Gamblin SJ. (Apr 2011). "Structure of mammalian AMPK and its regulation by ADP.". Nature 472 (7342): 230–233. doi:10.1038/nature06161. PMID 17851531.
- Chen L, Wang J, Zhang YY, Yan SF, Neumann D, Schlattner U, Wang ZX, Wu JW. (Jun 2012). "AMP-activated protein kinase undergoes nucleotide-dependent conformational changes". Nat Struct Mol Biol. 19 (7): 716–718. doi:10.1038/nsmb.2319.
- Thomson DM, Porter BB, Tall JH, Kim HJ, Barrow JR, Winder WW (January 2007). "Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice". Am. J. Physiol. Endocrinol. Metab. 292 (1): E196–202. doi:10.1152/ajpendo.00366.2006. PMID 16926377.
- Ojuka EO (May 2004). "Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle". Proc Nutr Soc 63 (2): 275–8. doi:10.1079/PNS2004339. PMID 15294043.
- Durante PE, Mustard KJ, Park SH, Winder WW, Hardie DG (July 2002). "Effects of endurance training on activity and expression of AMP-activated protein kinase isoforms in rat muscles". Am. J. Physiol. Endocrinol. Metab. 283 (1): E178–86. doi:10.1152/ajpendo.00404.2001. PMID 12067859.
- Bergeron R, Russell RR, Young LH, Ren JM, Marcucci M, Lee A, Shulman GI (May 1999). "Effect of AMPK activation on muscle glucose metabolism in conscious rats". Am. J. Physiol. 276 (5 Pt 1): E938–44. PMID 10329989.
- Winder WW (September 2001). "Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle". J. Appl. Physiol. 91 (3): 1017–28. PMID 11509493.
- Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D (October 2006). "Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase". J. Biol. Chem. 281 (43): 32207–16. doi:10.1074/jbc.M606357200. PMID 16943194.
- Gabriele V. Ronnett, Santosh Ramamurthy, Amy M. Kleman, Leslie E. Landree, and Susan Aja (May 2009). "AMPK in the Brain: Its Roles in Energy Balance and Neuroprotection". J Neurochem. 109 Suppl 1: 17–23. doi:10.1111/j.1471-4159.2009.05916.x. PMC 2925428. PMID 19393004.
- Florant, G.L., Fenn, A.M., Healy, J.E., Wilkerson, G.K., & Handa, R.J. 2010. To eat or not to eat: the effect of AICAR on food intake regulation in yellow-bellied marmots (Marmota flaviventris). JEB, 213, 2031-2037. http://jeb.biologists.org/content/213/12/2031.full.pdf+html.
- Wang, Y., Nishi, M., Doi, A., Shono, T., Furukawa, Y., Shimada, T., Furuta, H., Sasaki, H., & Nanjo, K. 2010. Ghrelin inhibits insulin secretion through the AMPK-UCP2 pathway in beta cells. FEBS letters, 584, 1503-8.
- Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (October 2001). "Role of AMP-activated protein kinase in mechanism of metformin action". J. Clin. Invest. 108 (8): 1167–74. doi:10.1172/JCI13505. PMC 209533. PMID 11602624.
- Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51(7):2074–81. doi:10.2337/diabetes.51.7.2074. PMID 12086935.
- Polleux, Franck. "The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation". Neuron. Retrieved 10 April 2013.
- Ma X, Egawa T, Kimura H, Karaike K, Masuda S, Iwanaka N, Hayashi T (April 2010). "Berberine-induced activation of 5'-adenosine monophosphate-activated protein kinase and glucose transport in rat skeletal muscles". Metabolism 59 (11): 1619–27. doi:10.1016/j.metabol.2010.03.009. PMID 20423742.
- Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB (April 2009). "Berberine suppresses proinflammatory responses through AMPK activation in macrophages". Am. J. Physiol. Endocrinol. Metab. 296 (4): E955–64. doi:10.1152/ajpendo.90599.2008. PMID 19208854.
- Kim WS, Lee YS, Cha SH, Jeong HW, Choe SS, Lee MR, Oh GT, Park HS, Lee KU, Lane MD, Kim JB (April 2009). "Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity". Am. J. Physiol. Endocrinol. Metab. 296 (4): E812–9. doi:10.1152/ajpendo.90710.2008. PMID 19176354.
- Liang KW, Yin SC, Ting CT, Lin SJ, Hsueh CM, Chen CY, Hsu SL (August 2008). "Berberine inhibits platelet-derived growth factor-induced growth and migration partly through an AMPK-dependent pathway in vascular smooth muscle cells". Eur. J. Pharmacol. 590 (1-3): 343–54. doi:10.1016/j.ejphar.2008.06.034. PMID 18590725.
- Zhou L, Wang X, Shao L, Yang Y, Shang W, Yuan G, Jiang B, Li F, Tang J, Jing H, Chen M (September 2008). "Berberine acutely inhibits insulin secretion from beta-cells through 3',5'-cyclic adenosine 5'-monophosphate signaling pathway". Endocrinology 149 (9): 4510–8. doi:10.1210/en.2007-1752. PMID 18511510.
- Corton JM, Gillespie JG, Hawley SA, Hardie DG (April 1995). "5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?". Eur. J. Biochem. 229 (2): 558–65. doi:10.1111/j.1432-1033.1995.0558k.x. PMID 7744080.
- Henin N, Vincent MF, Gruber HE, Van den Berghe G (April 1995). "Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase". FASEB J. 9 (7): 541–6. PMID 7737463.
- Henin N, Vincent MF, Van den Berghe G (June 1996). "Stimulation of rat liver AMP-activated protein kinase by AMP analogues". Biochim. Biophys. Acta 1290 (2): 197–203. doi:10.1016/0304-4165(96)00021-9. PMID 8645724.
- Sullivan JE, Brocklehurst KJ, Marley AE, Carey F, Carling D, Beri RK (October 1994). "Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase". FEBS Lett. 353 (1): 33–6. doi:10.1016/0014-5793(94)01006-4. PMID 7926017.
- Stein SC, Woods A, Jones NA, Davison MD, Carling D (February 2000). "The regulation of AMP-activated protein kinase by phosphorylation". Biochem. J. 345 (3): 437–43. doi:10.1042/0264-6021:3450437. PMC 1220775. PMID 10642499.
- Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP, Alessi DR, Hardie DG (2003). "Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade". J. Biol. 2 (4): 28. doi:10.1186/1475-4924-2-28. PMC 333410. PMID 14511394.
- Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (November 2003). "LKB1 is the upstream kinase in the AMP-activated protein kinase cascade". Curr. Biol. 13 (22): 2004–8. doi:10.1016/j.cub.2003.10.031. PMID 14614828.
- Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (March 2004). "The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress". Proc. Natl. Acad. Sci. U.S.A. 101 (10): 3329–35. doi:10.1073/pnas.0308061100. PMC 373461. PMID 14985505.
- Neumann D, Suter M, Tuerk R, Riek U, Wallimann T (July 2007). "Co-expression of LKB1, MO25alpha and STRADalpha in bacteria yield the functional and active heterotrimeric complex". Mol. Biotechnol. 36 (3): 220–31. doi:10.1007/s12033-007-0029-x. PMID 17873408.
- Davies SP, Helps NR, Cohen PT, Hardie DG (December 1995). "5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC". FEBS Lett. 377 (3): 421–5. doi:10.1016/0014-5793(95)01368-7. PMID 8549768.
- W. J. Ellingson, D. G. Chesser, and W. W. Winder Effects of 3-phosphoglycerate and other metabolites on the activation of AMP-activated protein kinase by LKB1-STRAD-MO25 Am J Physiol Endocrinol Metab February 1, 2007 292:(2) E400-E407; published ahead of print September 19, 2006, doi:10.1152/ajpendo.00322.2006
- Winder WW, Hardie DG (February 1996). "Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise". Am. J. Physiol. 270 (2 Pt 1): E299–304. PMID 8779952.
- Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T (November 2002). "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase". Nat. Med. 8 (11): 1288–95. doi:10.1038/nm788. PMID 12368907.
- Carling D, Hardie DG (June 1989). "The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase". Biochim. Biophys. Acta 1012 (1): 81–6. doi:10.1016/0167-4889(89)90014-1. PMID 2567185.
- Corton JM, Gillespie JG, Hardie DG (April 1994). "Role of the AMP-activated protein kinase in the cellular stress response". Curr. Biol. 4 (4): 315–24. doi:10.1016/S0960-9822(00)00070-1. PMID 7922340.
- Rasmussen BB, Winder WW (October 1997). "Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase". J. Appl. Physiol. 83 (4): 1104–9. PMID 9338417.
- Hurst D, Taylor EB, Cline TD, Greenwood LJ, Compton CL, Lamb JD, Winder WW (October 2005). "AMP-activated protein kinase kinase activity and phosphorylation of AMP-activated protein kinase in contracting muscle of sedentary and endurance-trained rats". Am. J. Physiol. Endocrinol. Metab. 289 (4): E710–5. doi:10.1152/ajpendo.00155.2005. PMID 15928023.
- Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ (August 1998). "Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport". Diabetes 47 (8): 1369–73. doi:10.2337/diabetes.47.8.1369. PMID 9703344.
- Hutber CA, Hardie DG, Winder WW (February 1997). "Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase". Am. J. Physiol. 272 (2 Pt 1): E262–6. PMID 9124333.
- Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Müller C, Carling D, Kahn BB (January 2002). "Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase". Nature 415 (6869): 339–43. doi:10.1038/415339a. PMID 11797013.
- Taylor EB, Hurst D, Greenwood LJ, Lamb JD, Cline TD, Sudweeks SN, Winder WW (December 2004). "Endurance training increases LKB1 and MO25 protein but not AMP-activated protein kinase kinase activity in skeletal muscle". Am. J. Physiol. Endocrinol. Metab. 287 (6): E1082–9. doi:10.1152/ajpendo.00179.2004. PMID 15292028.
- Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, Young LH, Semenkovich CF, Shulman GI (December 2001). "Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis". Am. J. Physiol. Endocrinol. Metab. 281 (6): E1340–6. PMID 11701451.
- Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI (December 2002). "AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation". Proc. Natl. Acad. Sci. U.S.A. 99 (25): 15983–7. doi:10.1073/pnas.252625599. PMC 138551. PMID 12444247.
- Holmes BF, Kurth-Kraczek EJ, Winder WW (November 1999). "Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle". J. Appl. Physiol. 87 (5): 1990–5. PMID 10562646.
- Ojuka EO, Jones TE, Nolte LA, Chen M, Wamhoff BR, Sturek M, Holloszy JO (May 2002). "Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+)". Am. J. Physiol. Endocrinol. Metab. 282 (5): E1008–13. doi:10.1152/ajpendo.00512.2001. PMID 11934664.
- Stoppani J, Hildebrandt AL, Sakamoto K, Cameron-Smith D, Goodyear LJ, Neufer PD (December 2002). "AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle". Am. J. Physiol. Endocrinol. Metab. 283 (6): E1239–48. doi:10.1152/ajpendo.00278.2002. PMID 12388122.
- Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO (June 2000). "Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle". J. Appl. Physiol. 88 (6): 2219–26. PMID 10846039.
- Ouchi N, Shibata R, Walsh K (April 2005). "AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle". Circ. Res. 96 (8): 838–46. doi:10.1161/01.RES.0000163633.10240.3b. PMID 15790954.
- Hayashi T, Hirshman MF, Fujii N, Habinowski SA, Witters LA, Goodyear LJ (April 2000). "Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism". Diabetes 49 (4): 527–31. doi:10.2337/diabetes.49.4.527. PMID 10871188.
- Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW (August 1999). "5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle". Diabetes 48 (8): 1667–71. doi:10.2337/diabetes.48.8.1667. PMID 10426389.
- Merrill GF, Kurth EJ, Hardie DG, Winder WW (December 1997). "AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle". Am. J. Physiol. 273 (6 Pt 1): E1107–12. PMID 9435525.
- Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L (October 2000). "Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia". Curr. Biol. 10 (20): 1247–55. doi:10.1016/S0960-9822(00)00742-9. PMID 11069105.
- Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, Oh KS, Koh EH, Won JC, Kim MS, Oh GT, Yoon M, Lee KU, Park JY (February 2006). "AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1". Biochem. Biophys. Res. Commun. 340 (1): 291–5. doi:10.1016/j.bbrc.2005.12.011. PMID 16364253.
- Suwa M, Egashira T, Nakano H, Sasaki H, Kumagai S (December 2006). "Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo". J. Appl. Physiol. 101 (6): 1685–92. doi:10.1152/japplphysiol.00255.2006. PMID 16902066.
- Ojuka EO, Nolte LA, Holloszy JO (March 2000). "Increased expression of GLUT-4 and hexokinase in rat epitrochlearis muscles exposed to AICAR in vitro". J. Appl. Physiol. 88 (3): 1072–5. PMID 10710405.
- Taylor EB, Lamb JD, Hurst RW, Chesser DG, Ellingson WJ, Greenwood LJ, Porter BB, Herway ST, Winder WW (December 2005). "Endurance training increases skeletal muscle LKB1 and PGC-1alpha protein abundance: effects of time and intensity". Am. J. Physiol. Endocrinol. Metab. 289 (6): E960–8. doi:10.1152/ajpendo.00237.2005. PMID 16014350.
- Jørgensen, SB; Treebak, JT; Viollet, B; Schjerling, P; Vaulont, S; Wojtaszewski, JFP; Richter, EA (2007). "Role of AMPKα2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle". Endocrinology and metabolism 292 (1): E331–E339. doi:10.1152/ajpendo.00243.2006.
- Röckl KS, Hirshman MF, Brandauer J, Fujii N, Witters LA, Goodyear LJ (2007). "Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift". Diabetes 56 (8): 2062–2069. doi:10.2337/db07-0255.
- Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (October 2007). "Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress". Cell Metab. 6 (4): 280–93. doi:10.1016/j.cmet.2007.08.011. PMID 17908557.
- Sakamoto K, Göransson O, Hardie DG, Alessi DR (August 2004). "Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR". Am. J. Physiol. Endocrinol. Metab. 287 (2): E310–7. doi:10.1152/ajpendo.00074.2004. PMID 15068958.
- Taylor EB, Ellingson WJ, Lamb JD, Chesser DG, Winder WW (June 2005). "Long-chain acyl-CoA esters inhibit phosphorylation of AMP-activated protein kinase at threonine-172 by LKB1/STRAD/MO25". Am. J. Physiol. Endocrinol. Metab. 288 (6): E1055–61. doi:10.1152/ajpendo.00516.2004. PMID 15644453.
- Hardie DG, Hawley SA (December 2001). "AMP-activated protein kinase: the energy charge hypothesis revisited". BioEssays 23 (12): 1112–9. doi:10.1002/bies.10009. PMID 11746230.
- Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferré P, Birnbaum MJ, Stuck BJ, Kahn BB (April 2004). "AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus". Nature 428 (6982): 569–74. doi:10.1038/nature02440. PMID 15058305.
- AMP-activated protein kinase at the US National Library of Medicine Medical Subject Headings (MeSH)
- EC 220.127.116.11