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AMPK in Health and Disease

Steinberg, Gregory R., Kemp, Bruce E.·2009·Physiological Reviews

DOI 10.1152/physrev.00011.2008

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Abstract

The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

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“The mammalian AMPK domain limits were established experimentally by partial proteolysis (395), and a stable rat 1(68-163) fragment was expressed and crystallized in the presence of -cyclodextrin (an 1-4 linked heptaglucan), as had previously been performed for other starch binding domain structural studies (396).”
BackgroundMethodInfluential
AMP-Activated Protein Kinase is Highly Expressed in Neurons in the Developing Rat Brain and Promotes Neuronal Survival Following Glucose Deprivation
Culmsee, C., monnig, J., Kemp, B. E., & Mattson, M. P. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:17:1:45 · Cited by 340
Self-citation
Structure of the Autoinhibited Kinase Domain of CaMKII and SAXS Analysis of the Holoenzyme
Rosenberg, O. S., Deindl, S., Sung, R.-J., Nairn, A. C., & Kuriyan, J. (2005) · Cell · doi:10.1016/j.cell.2005.10.029 · Cited by 333
Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke
McCullough, L. D., Zeng, Z., Li, H., Landree, L. E., McFadden, J., & Ronnett, G. V. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m409985200 · Cited by 333
A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias
Hudson, E. R., Pan, D. A., James, J., Lucocq, J. M., Hawley, S. A., Green, K. A., Baba, O., Terashima, T., & Hardie, D. G. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00249-5 · Cited by 332
Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte
Chan, A. Y. M., Soltys, C.-L. M., Young, M. E., Proud, C. G., & Dyck, J. R. B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403528200 · Cited by 331
Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content
Bruce, C. R., Thrush, A. B., Mertz, V. A., Bezaire, V., Chabowski, A., Heigenhauser, G. J. F., & Dyck, D. J. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00587.2005 · Cited by 328
Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes
Tamás, P., Hawley, S. A., Clarke, R. G., Mustard, K. J., Green, K., Hardie, D. G., & Cantrell, D. A. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052469 · Cited by 328
The 5′-AMP-activated Protein Kinase γ3 Isoform Has a Key Role in Carbohydrate and Lipid Metabolism in Glycolytic Skeletal Muscle
Barnes, B. R., Marklund, S., Steiler, T. L., Walter, M., Hjälm, Amarger, V., Mahlapuu, M., Leng, Y., Johansson, C., Galuska, D., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405533200 · Cited by 317
Distinct Signals Regulate AS160 Phosphorylation in Response to Insulin, AICAR, and Contraction in Mouse Skeletal Muscle
Kramer, H. F., Witczak, C. A., Fujii, N., Jessen, N., Taylor, E. B., Arnolds, D. E., Sakamoto, K., Hirshman, M. F., & Goodyear, L. J. (2006) · Diabetes · doi:10.2337/db06-0150 · Cited by 315
Acute IL-6 Treatment Increases Fatty Acid Turnover in Elderly Humans in Vivo and in Tissue Culture in Vitro
Petersen, E. W., Carey, A. L., Sacchetti, M., Steinberg, G. R., Macaulay, S. L., Febbraio, M. A., & Pedersen, B. K. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00257.2004 · Cited by 311
Self-citation
Calcium Induces Increases in Peroxisome Proliferator-activated Receptor γ Coactivator-1α and Mitochondrial Biogenesis by a Pathway Leading to p38 Mitogen-activated Protein Kinase Activation
Wright, D. C., Geiger, P. C., Han, D.-H., Jones, T. E., & Holloszy, J. O. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611252200 · Cited by 309
Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects with Type 2 Diabetes
Sriwijitkamol, A., Coletta, D. K., Wajcberg, E., Balbontin, G. B., Reyna, S. M., Barrientes, J., Eagan, P. A., Jenkinson, C. P., Cersosimo, E., DeFronzo, R. A., et al. (2007) · Diabetes · doi:10.2337/db06-1119 · Cited by 304
Regulation of mammalian acetyl-CoA carboxylase
Munday, M. R. (2002) · Biochemical Society Transactions · doi:10.1042/bst0301059 · Cited by 301
The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase
Carling, D., & Grahame Hardie, D. (1989) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/0167-4889(89)90014-1 · Cited by 296
Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues
LeBrasseur, N. K., Kelly, M., Tsao, T.-S., Farmer, S. R., Saha, A. K., Ruderman, N. B., & Tomas, E. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00453.2005 · Cited by 276
Effects of α‐AMPK knockout on exercise‐induced gene activation in mouse skeletal muscle
Jørgensen, S. B., Wojtaszewski, J. F. P., Viollet, B., Andreelli, F., Birk, J. B., Hellsten, Y., Schjerling, P., Vaulont, S., Neufer, P. D., Richter, E. A., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-3144fje · Cited by 274
Increased Phosphorylation of Akt Substrate of 160 kDa (AS160) in Rat Skeletal Muscle in Response to Insulin or Contractile Activity
Bruss, M. D., Arias, E. B., Lienhard, G. E., & Cartee, G. D. (2005) · Diabetes · doi:10.2337/diabetes.54.1.41 · Cited by 273 · cited 4×
“Since the constitutively active AMPK fragment 1 (1-312) is not activated by the PT1 compound, it is proposed that PT1 acts by reversing the autoinhibition of the AIS (313-335).”
BackgroundInfluential
Glycogen-Dependent Effects of 5-Aminoimidazole-4-Carboxamide (AICA)-Riboside on AMP-Activated Protein Kinase and Glycogen Synthase Activities in RatSkeletal Muscle
Wojtaszewski, J. F. P., Jørgensen, S. B., Hellsten, Y., Hardie, D. G., & Richter, E. A. (2002) · Diabetes · doi:10.2337/diabetes.51.2.284 · Cited by 261
Activation of 5′-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase Iɛ (CKIɛ)-dependent Degradation of Clock Protein mPer2
Um, J. H., Yang, S., Yamazaki, S., Kang, H., Viollet, B., Foretz, M., & Chung, J. H. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c700070200 · Cited by 244
Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models
Viollet, B., Andreelli, F., Jørgensen, S. B., Perrin, C., Flamez, D., Mu, J., Wojtaszewski, J. F. P., Schuit, F. C., Birnbaum, M., Richter, E., et al. (2003) · Biochemical Society Transactions · doi:10.1042/bst0310216 · Cited by 241
5′-AMP-activated Protein Kinase Phosphorylates IRS-1 on Ser-789 in Mouse C2C12 Myotubes in Response to 5-Aminoimidazole-4-carboxamide Riboside
Jakobsen, S. N., Hardie, D. G., Morrice, N., & Tornqvist, H. E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100483200 · Cited by 238 · cited 4×
“One possible explanation for the enhanced insulin sensitivity postexercise relates to the finding that AMPK phosphorylates insulin receptor substrate 1 (IRS-1) at Ser789 in vitro and that AICAR treatment in C2C12 muscle cells increases IRS-1 Ser-789 phosphorylation and insulin-stimulated IRS-1 associated PI3K activity…”
BackgroundInfluential
Phosphorylation of rat muscle acetyl-coa carboxylase by amp-activated protein kinase and protein kinase A
Winder, W. W., Wilson, H. A., Hardie, D. G., Rasmussen, B. B., Hutber, C. A., Call, G. B., Clayton, R. D., Conley, L. M., Yoon, S., & Zhou, B. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.82.1.219 · Cited by 237
Rapid transformation of white adipocytes into fat-oxidizing machines
Orci, L., Cook, W. S., Ravazzola, M., Wang, M.-Y., Park, B.-H., Montesano, R., & Unger, R. H. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308258100 · Cited by 234
Molecular disruption of hypothalamic nutrient sensing induces obesity
He, W., Lam, T. K. T., Obici, S., & Rossetti, L. (2006) · Nature Neuroscience · doi:10.1038/nn1626 · Cited by 233 · cited 4×
“Since the constitutively active AMPK fragment 1 (1-312) is not activated by the PT1 compound, it is proposed that PT1 acts by reversing the autoinhibition of the AIS (313-335).”
BackgroundInfluential
AMP-activated Protein Kinase Regulates HNF4α Transcriptional Activity by Inhibiting Dimer Formation and Decreasing Protein Stability
Hong, Y. H., Varanasi, U. S., Yang, W., & Leff, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304112200 · Cited by 220
Adiponectin Sensitizes Insulin Signaling by Reducing p70 S6 Kinase-mediated Serine Phosphorylation of IRS-1
Wang, C., Mao, X., Wang, L., Liu, M., Wetzel, M. D., Guan, K.-L., Dong, L. Q., & Liu, F. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700098200 · Cited by 210
Leptin increases FA oxidation in lean but not obese human skeletal muscle: evidence of peripheral leptin resistance
Steinberg, G. R., Parolin, M. L., Heigenhauser, G. J. F., & Dyck, D. J. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00542.2001 · Cited by 207
Self-citation
Skeletal Muscle-Selective Knockout of LKB1 Increases Insulin Sensitivity, Improves Glucose Homeostasis, and Decreases TRB3
Koh, H.-J., Arnolds, D. E., Fujii, N., Tran, T. T., Rogers, M. J., Jessen, N., Li, Y., Liew, C. W., Ho, R. C., Hirshman, M. F., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00979-06 · Cited by 202
PPARα is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue
Lee, Y., Yu, X., Gonzales, F., Mangelsdorf, D. J., Wang, M.-Y., Richardson, C., Witters, L. A., & Unger, R. H. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182420899 · Cited by 181
Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR
Geraghty, K. M., Chen, S., Harthill, J. E., Ibrahim, A. F., Toth, R., Morrice, N. A., Vandermoere, F., Moorhead, G. B., Hardie, D. G., & MacKintosh, C. (2007) · Biochemical Journal · doi:10.1042/bj20070649 · Cited by 181
Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-α
Bruce, C. R., & Dyck, D. J. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00150.2004 · Cited by 178 · cited 4×
“Since the constitutively active AMPK fragment 1 (1-312) is not activated by the PT1 compound, it is proposed that PT1 acts by reversing the autoinhibition of the AIS (313-335).”
BackgroundInfluential
AMP-activated Protein Kinase α2 Activity Is Not Essential for Contraction- and Hyperosmolarity-induced Glucose Transport in Skeletal Muscle
Fujii, N., Hirshman, M. F., Kane, E. M., Ho, R. C., Peter, L. E., Seifert, M. M., & Goodyear, L. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504208200 · Cited by 177
Malonyl-coa and carnitine in regulation of fat oxidation in human skeletal muscle during exercise
Roepstorff, C., Halberg, N., Hillig, T., Saha, A. K., Ruderman, N. B., Wojtaszewski, J. F. P., Richter, E. A., & Kiens, B. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00379.2004 · Cited by 173
On the incorporation of Mg and the role of oxygen, silicon, and hydrogen in GaN prepared by reactive molecular beam epitaxy
Kim, W., Botchkarev, A. E., Salvador, A., Popovici, G., Tang, H., & Morkoç, H. (1997) · Journal of Applied Physics · doi:10.1063/1.365801 · Cited by 168
Exercise Increases Nuclear AMPK α2 in Human Skeletal Muscle
McGee, S. L., Howlett, K. F., Starkie, R. L., Cameron-Smith, D., Kemp, B. E., & Hargreaves, M. (2003) · Diabetes · doi:10.2337/diabetes.52.4.926 · Cited by 160
Self-citation
AMPK‐independent pathways regulate skeletal muscle fatty acid oxidation
Dzamko, N., Schertzer, J. D., Ryall, J. G., Steel, R., Macaulay, S. L., Wee, S., Chen, Z., Michell, B. J., Oakhill, J. S., Watt, M. J., et al. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.159814 · Cited by 147
Self-citation
Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice.
Thomson, D. M., Porter, B. B., Tall, J. H., Kim, H.-J., Barrow, J. R., & Winder, W. W. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00366.2006 · Cited by 146
Diminished overload-induced hypertrophy in aged fast-twitch skeletal muscle is associated with AMPK hyperphosphorylation
Thomson, D. M., & Gordon, S. E. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00811.2004 · Cited by 131
AMP-Activated Protein Kinase Is Not Down-Regulated in Human Skeletal Muscle of Obese Females
Steinberg, G. R., Smith, A. C., van Denderen, B. J. W., Chen, Z., Murthy, S., Campbell, D. J., Heigenhauser, G. J. F., Dyck, D. J., & Kemp, B. E. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0308 · Cited by 97
Self-citation
Selective suppression of AMP-activated protein kinase in skeletal muscle: update on ‘lazy mice’
Mu, J., Barton, E. R., & Birnbaum, M. J. (2003) · Biochemical Society Transactions · doi:10.1042/bst0310236 · Cited by 93
Cloning and characterization of mouse 5′-AMP-activated protein kinase γ3 subunit
Yu, H., Fujii, N., Hirshman, M. F., Pomerleau, J. M., & Goodyear, L. J. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00319.2003 · Cited by 67
Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet
Tanaka, T., Masuzaki, H., Yasue, S., Ebihara, K., Shiuchi, T., Ishii, T., Arai, N., Hirata, M., Yamamoto, H., Hayashi, T., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.04.004 · Cited by 62

Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling
Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L., Huang, M. T.-H., Brickey, W. J., & Ting, J. P.-Y. (2011) · Nature Immunology · doi:10.1038/ni.2022 · Cited by 1,698
Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network
Scarpulla, R. C. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.09.019 · Cited by 1,281
AMPK and SIRT1: a long-standing partnership?
Ruderman, N. B., Julia Xu, X., Nelson, L., Cacicedo, J. M., Saha, A. K., Lan, F., & Ido, Y. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00745.2009 · Cited by 903
Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889
Self-citation
AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan
Salminen, A., Hyttinen, J. M. T., & Kaarniranta, K. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0748-0 · Cited by 866

See all 1,637

Authors: Steinberg, G. R., & Kemp, B. E.
Venue: Physiological Reviews
Publisher: American Physiological Society
Published: 2009-07
Volume: 89
Issue: 3
Pages: 1025-1078
ISSN: 0031-9333 (ISSN-L)
1522-1210
DOI: 10.1152/physrev.00011.2008
OpenAlex: W2150551377
Cited by: 1,637
References: 121
FWCI: 5.07
Type: journal article
Language: en
Open access: closed

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AMPK in Health and Disease

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