AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 188.8.131.52) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 and SnRK1 in yeast and plants, respectively. 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. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, activation of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells.
|[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase|
AMP-activated protein kinase
|PDB structures||RCSB PDB PDBe PDBsum|
AMPK is a heterotrimeric protein complex that 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:
Due to the presence of isoforms of its components, there are 12 versions of AMPK in mammals, each of which can have different tissue localizations, and different functions under different conditions. AMPK is regulated allosterically and by post-translational modification, which work together
If residue T172 of AMPK's α-subunit is phosphorylated, AMPK is activated; access to that residue by phosphatases is blocked if AMP or ADP can block access for and ATP can displace AMP and ADP. That residue is phosphorylated by at least three kinases (liver kinase B1 (LKB1) which works in a complex with STRAD and MO25, Calcium/calmodulin-dependent protein kinase kinase II-(CAMKK2), and TGFβ-activated kinase 1 (TAK1)) and is dephosphorylated by three phosphatases (protein phosphatase 2A (PP2A); protein phosphatase 2C (PP2C) and Mg2+-/Mn2+-dependent protein phosphatase 1E (PPM1E)).
AMPK is regulated allosterically mostly by competitive binding on its gamma subunit between ATP (which allows phosphatase access to T172) and AMP or ADP (each of which blocks access to phosphatases). It also appears that AMPK is a sensor of AMP/ATP or ADP/ATP ratios and thus cell energy level. Regulation of AMPK by CaMKK2 requires a direct interaction of these two proteins via their kinase domains. The interaction of CaMKK2 with AMPK only involves the alpha and beta subunits of AMPK (AMPK gamma is absent from the CaMKK2 complex), thus rendering regulation of AMPK in this context to changes in calcium levels but not AMP or ADP.
It is also regulated by several protein-protein interactions, and may either by activated or inhibited by oxidative factors; the role of oxidation in regulating AMPK was controversial as of 2016.
When AMPK phosphorylates acetyl-CoA carboxylase 1 (ACC1) or sterol regulatory element-binding protein 1c (SREBP1c), it inhibits synthesis of fatty acids, cholesterol, and triglycerides, and activates fatty acid uptake and β-oxidation.
AMPK stimulates glucose uptake in skeletal muscle by phosphorylating Rab-GTPase-activating protein TBC1D1, which ultimately induces fusion of GLUT4 vesicles with the plasma membrane. AMPK stimulates glycolysis by activating phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/3 and activating phosphorylation of glycogen phosphorylase, and it inhibits glycogen synthesis through inhibitory phosphorylation of glycogen synthase. In the liver, AMPK inhibits gluconeogenesis by inhibiting transcription factors including hepatocyte nuclear factor 4 (HNF4) and CREB regulated transcription coactivator 2 (CRTC2).
AMPK inhibits the energy-intensive protein biosynthesis process and can also force a switch from cap-dependent translation to cap-independent translation, which requires less energy, by phosphorylation of TSC2, RPTOR, transcription initiation factor 1A.66, and eEF2K. When TSC2 is activated it inhibits mTORC1. As a result of inhibition of mTORC1 by AMPK, protein synthesis comes to a halt. Activation of AMPK signifies low energy within the cell, so all of the energy consuming pathways like protein synthesis are inhibited, and pathways that generate energy are activated to restore appropriate energy levels in the cell.
AMPK activates autophagy by directly and indirectly activating ULK1. AMPK also appears to stimulate mitochondrial biogenesis by regulating PGC-1α which in turn promotes gene transcription in mitochondria. AMPK also activates anti-oxidant defenses.
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 a fatty-acid oxidation approach to ATP generation as opposed to a glycolytic approach. AMPK accomplishes this transition to the oxidative mode of metabolism by upregulating and activating oxidative enzymes such as hexokinase II, PPARalpha, PPARdelta, PGC-1, UCP-3, 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 spanEdit
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 AICA ribonucleotide (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, maintaining 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.
Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional regulator for genes involved in fatty acid oxidation, gluconeogenesis, and is considered the master regulator for mitochondrial biogenesis.
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.
Glucose sensing systemsEdit
Loss of AMPK has been reported to alter the sensitivity of glucose sensing cells, through poorly defined mechanisms. Loss of the AMPKα2 subunit in pancreatic beta cells and hypothalamic neurons decreases the sensitivity of these cells to changes in extracellular glucose concentration. Moreover, exposure of rats to recurrent bouts of insulin induced hypoglycaemia/glucopenia, reduces the activation of AMPK within the hypothalamus, whilst also suppressing the counterregulatory response to hypoglycaemia.  Pharmacological activation of AMPK by delivery of AMPK activating drug AICAR, directly into the hypothalamus can increase the counterregulatory response to hypoglycaemia.
Controversy over role in adaption to exercise/trainingEdit
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, 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 mitochondrial biogenesis, upregulation of GLUT-4, UCP-3, Hexokinase II along with 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 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, due to previous adaptations to training, AMPK will not be activated, and further adaptation will not occur, until the intracellular ATP levels become depleted from an even higher intensity energy challenge than prior to those previous adaptations.
- 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. doi:10.1152/ajpendo.1999.277.1.E1. 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. Bibcode:2007Natur.449..496X. 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. Bibcode:2011Natur.472..230X. doi:10.1038/nature09932. PMC 3078618. PMID 21399626.
- 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. PMID 22659875.
- Jeon, SM (15 July 2016). "Regulation and function of AMPK in physiology and diseases". Experimental & Molecular Medicine. 48 (7): e245. doi:10.1038/emm.2016.81. PMC 4973318. PMID 27416781.
- Hardie DG, Ross FA, Hawley SA (March 2012). "AMPK: a nutrient and energy sensor that maintains energy homeostasis". Nature Reviews. Molecular Cell Biology. 13 (4): 251–62. doi:10.1038/nrm3311. PMC 5726489. PMID 22436748.
- 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. doi:10.1152/ajpendo.2001.281.6.e1340. 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. Bibcode:2002PNAS...9915983Z. 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. doi:10.1152/jappl.19184.108.40.2060. 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.
- 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.
- 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. doi:10.1152/jappl.2000.88.6.2219. 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, 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.
- 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. doi:10.1152/jappl.2000.88.3.1072. PMID 10710405.
- Giordano Attianese GM, Desvergne B (2008). "AMPK and PPARdelta agonists are exercise mimetics". Cell. 134 (3): 405–415. doi:10.1016/j.cell.2008.06.051. PMC 2706130. PMID 18674809.
- 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.
- 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.
- 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. doi:10.1152/ajpendo.1997.272.2.E262. PMID 9124333.
- 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.
- 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 JF, Richter EA (January 2007). "Role of AMPKalpha2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle". American Journal of Physiology. Endocrinology and Metabolism. 292 (1): E331–9. doi:10.1152/ajpendo.00243.2006. PMID 16954334.
- Röckl KS, Hirshman MF, Brandauer J, Fujii N, Witters LA, Goodyear LJ (August 2007). "Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift". Diabetes. 56 (8): 2062–9. doi:10.2337/db07-0255. PMID 17513699.
- 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.
- Winder WW (September 2001). "Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle". J. Appl. Physiol. 91 (3): 1017–28. doi:10.1152/jappl.2001.91.3.1017. PMID 11509493.
- 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.
- 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. Bibcode:2004Natur.428..569M. doi:10.1038/nature02440. PMID 15058305.
- 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.
- Sun G, Tarasov AI, McGinty J, McDonald A, da Silva Xavier G, Gorman T, Marley A, French PM, Parker H, Gribble F, Reimann F, Prendiville O, Carzaniga R, Viollet B, Leclerc I, Rutter GA (2010). "Ablation of AMP-activated protein kinase alpha1 and alpha2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo". Diabetologia. 53 (5): 924–36. doi:10.1007/s00125-010-1692-1. PMC 4306708. PMID 20221584.
- Beall C, Piipari K, Al-Qassab H, Smith MA, Parker N, Carling D, Viollet B, Withers DJ, Ashford ML (2010). "Loss of AMP-activated protein kinase alpha2 subunit in mouse beta-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia". Biochem. J. 429 (2): 323–33. doi:10.1042/BJ20100231. PMC 2895783. PMID 20465544.
- Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, Clements M, Al-Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford ML, Carling D, Withers DJ (2007). "AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons". J. Clin. Invest. 117 (8): 2325–36. doi:10.1172/JCI31516. PMC 1934578. PMID 17671657.
- Beall C, Hamilton DL, Gallagher J, Logie L, Wright K, Soutar MP, Dadak S, Ashford FB, Haythorne E, Du Q, Jovanović A, McCrimmon RJ, Ashford ML (2012). "Mouse hypothalamic GT1-7 cells demonstrate AMPK-dependent intrinsic glucose-sensing behaviour". Diabetologia. 55 (9): 2432–44. doi:10.1007/s00125-012-2617-y. PMC 3411292. PMID 22760787.
- Alquier T, Kawashima J, Tsuji Y, Kahn BB (2007). "Role of hypothalamic adenosine 5'-monophosphate-activated protein kinase in the impaired counterregulatory response induced by repetitive neuroglucopenia". Endocrinology. 148 (3): 1367–75. doi:10.1210/en.2006-1039. PMID 17185376.
- McCrimmon RJ, Shaw M, Fan X, Cheng H, Ding Y, Vella MC, Zhou L, McNay EC, Sherwin RS (2008). "Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia". Diabetes. 57 (2): 444–50. doi:10.2337/db07-0837. PMID 17977955.
- Fan X, Ding Y, Brown S, Zhou L, Shaw M, Vella MC, Cheng H, McNay EC, Sherwin RS, McCrimmon RJ (2009). "Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes". Am. J. Physiol. Regul. Integr. Comp. Physiol. 296 (6): R1702–8. doi:10.1152/ajpregu.90600.2008. PMC 2692788. PMID 19357294.