Calcium/calmodulin-dependent protein kinase kinase 2 regulates hepatic fuel metabolism

Journal article

Stork, Britanny A., Dean, Adam, Ortiz, Andrea R., Saha, Pradip, Putluri, Nagireddy, Planas-Silva, Maricarmen D., Mahmud, Iqbal, Rajapakshe, Kimal, Coarfa, Cristian, Knapp, Stefan, Lorenzi, Philip L., Kemp, Bruce E., Turk, Benjamin E., Scott, John W., Means, Anthony R. and York, Brian. (2022). Calcium/calmodulin-dependent protein kinase kinase 2 regulates hepatic fuel metabolism. Molecular Metabolism. 62, p. Article 101513. https://doi.org/10.1016/j.molmet.2022.101513
AuthorsStork, Britanny A., Dean, Adam, Ortiz, Andrea R., Saha, Pradip, Putluri, Nagireddy, Planas-Silva, Maricarmen D., Mahmud, Iqbal, Rajapakshe, Kimal, Coarfa, Cristian, Knapp, Stefan, Lorenzi, Philip L., Kemp, Bruce E., Turk, Benjamin E., Scott, John W., Means, Anthony R. and York, Brian
Abstract

Objective
The liver is the primary internal metabolic organ that coordinates whole body energy homeostasis in response to feeding and fasting. Genetic ablation or pharmacological inhibition of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) has been shown to significantly improve hepatic health and peripheral insulin sensitivity upon overnutrition with high fat diet. However, the precise molecular underpinnings that explain this metabolic protection have remained largely undefined.

Methods
To characterize the role of CaMKK2 in hepatic metabolism, we developed and challenged liver-specific CaMKK2 knockout (CaMKK2LKO) mice with high fat diet and performed glucose and insulin tolerance tests to evaluate peripheral insulin sensitivity. We used a combination of RNA-Sequencing, glucose and fatty acid istotopic tracer studies, a newly developed Seahorse assay for measuring the oxidative capacity of purified peroxisomes, and a degenerate peptide libarary to identify putative CaMKK2 substrates that mechanistically explain the protective effects of hepatic CaMKK2 ablation.

Results
Consistent with previous findings, we show that hepatic CaMKK2 ablation significantly improves indices of peripheral insulin sensitivity. Mechanistically, we found that CaMKK2 phosphorylates and regulates GAPDH to promote glucose metabolism and PEX3 to blunt peroxisomal fatty acid catabolism in the liver.

Conclusion
CaMKK2 is a central metabolic fuel sensor in the liver that significantly contributes to whole body systems metabolism.

Keywordsinsulin resistance; glucose metabolism; fatty acid metabolism; peroxisome; kinase signaling
Year2022
JournalMolecular Metabolism
Journal citation62, p. Article 101513
PublisherElsevier GmbH
ISSN2212-8778
Digital Object Identifier (DOI)https://doi.org/10.1016/j.molmet.2022.101513
PubMed ID35562082
Scopus EID2-s2.0-85131045048
PubMed Central IDPMC9157561
Open accessPublished as ‘gold’ (paid) open access
Page range1-15
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online11 May 2022
Publication process dates
Accepted05 May 2022
Deposited17 Mar 2023
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AMPK signaling to acetyl-CoA carboxylase is required for fasting - and cold-induced appetite but not thermogenesis
Galic, Sandra, Loh, Kim, Murray-Segal, Lisa, Steinberg, Gregory R., Andrews, Zane B. and Kemp, Bruce. (2018). AMPK signaling to acetyl-CoA carboxylase is required for fasting - and cold-induced appetite but not thermogenesis. eLife. 7, pp. 1 - 22. https://doi.org/10.7554/eLife.32656
Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4
Ngoei, Kevin R.W., Langendorf, Christopher G., Ling, Naomi, Hoque, Ashfaqul, Johnson, Swapna, Camerino, Michelle C., Walker, Scott R., Bozikis, Ylva E., Dite, Toby A., Ovens, Ashley J., Smiles, William, Jacobs, Roxane, Huang, He, Parker, Michael W., Scott, John W., Rider, Mark H., Foitzik, Richard C., Kemp, Bruce, Baell, Jonathan B. and Oakhill, Jonathan S.. (2018). Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4. Cell Chemical Biology. 25(6), pp. 728 - 737. https://doi.org/10.1016/j.chembiol.2018.03.008
AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation
Lepropre, Sophie, Kautbally, Shakeel, Octave, Marie, Ginion, Audrey, Onselaer, Marie-Blanche, Steinberg, Gregory R., Kemp, Bruce E., Hego, Alexandre, Wéra, Odile, Brouns, Sanne, Swieringa, Frauke, Giera, Martin, Darley-Usmar, Victor M., Ambroise, Jérôme, Guigas, Bruno, Heemskerk, Johan, Bertrand, Luc, Oury, Cécile, Beauloye, Christophe and Horman, Sandrine. (2018). AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation. Blood. 132(11), pp. 1180 - 1192. https://doi.org/10.1182/blood-2018-02-831503
The spectrum of neurological and white matter changes and premutation status categories of older male carriers of the FMR1 alleles are linked to genetic (CGG and FMR1 mRNA) and cellular stress (AMPK) markers
Loesch, Danuta Z., Trost, Nicholas, Bui, Minh Q., Hammersley, Eleanor, Lay, Sui T., Annesley, Sarah J., Sanislav, Oana, Allan, Claire Y., Tassone, Flora, Chen, Zhi-Ping, Ngoei, Kevin R. W., Kemp, Bruce E., Francis, David, Fisher, Paul R. and Storey, Elsdon. (2018). The spectrum of neurological and white matter changes and premutation status categories of older male carriers of the FMR1 alleles are linked to genetic (CGG and FMR1 mRNA) and cellular stress (AMPK) markers. Frontiers in Genetics. 9, pp. 1 - 12. https://doi.org/10.3389/fgene.2018.00531
Visualizing AMPK drug binding sites through crystallization of full-length phosphorylated α2β1γ1 heterotrimer
Langendorf, Christopher G., Oakhill, Jonathan S. and Kemp, Bruce E.. (2018). Visualizing AMPK drug binding sites through crystallization of full-length phosphorylated α2β1γ1 heterotrimer. In In D. Neumann and B. Viollet (Ed.). AMPK: Methods and protocol pp. 15 - 27 Humana Press, Inc.. https://doi.org/10.1007/978-1-4939-7598-3_2
Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells
Hoque, Ashfaqul, Sivakumaran, Priyadharshini, Bond, Simon T., Ling, Naomi, Kong, Anne M., Scott, John W., Bandara, Nadeeka, Hernandez, Damian, Liu, Guei-Sheung, Wong, Raymond, Ryan, Michael T., Hausenloy, Derek, Kemp, Bruce, Oakhill, Jonathan S., Drew, Brian, Pebay, Alice and Lim, Shiang Y.. (2018). Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells. Cell Death Discovery. 4(39), pp. 1 - 13. https://doi.org/10.1038/s41420-018-0042-9
AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965
Dite, Toby A., Langendorf, Christopher, Hoque, Ashfaqul, Galic, Sandra, Rebello, Richard J., Ovens, Ashley J., Lindqvist, Lisa M., Ngoei, Kevin R.W., Ling, Naomi, Furic, Luc, Kemp, Bruce, Scott, John W. and Oakhill, Jonathan S.. (2018). AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965. Journal of Biological Chemistry. 293(23), pp. 8874 - 8885. https://doi.org/10.1074/jbc.RA118.003547
Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo
Madiraju, Anila K., Qiu, Yang, Perry, Rachel J., Rahimi, Yasmeen, Zhang, Xian-Man, Zhang, Dongyan, Camporez, João-Paulo G., Cline, Gary W., Butrico, Gina M., Kemp, Bruce, Casals, Gregori, Steinberg, Gregory R., Vatner, Daniel F., Petersen, Kitt F. and Shulman, Gerald I.. (2018). Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nature Medicine. 24(9), pp. 1384-1394. https://doi.org/10.1038/s41591-018-0125-4
1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors
Asquith, Christopher R.M., Godoi, Paulo H., Counago, Rafael M., Laitinen, Tuomo, Scott, John W., Langendorf, Christopher G., Oakhill, Jonathan S., Drewry, David H., Zuercher, William J., Koutentis, Panayiotis A., Willson, Timothy M. and Kalogirou, Andreas S.. (2018). 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors. Molecules. 23(5), pp. 1 - 23. https://doi.org/10.3390/molecules23051221
Impact of genetic variation on human CaMKK2 regulation by Ca2+ -calmodulin and multisite phosphorylation
O'Brien, Matthew, Oakhill, Jonathan S., Ling, Naomi, Langendorf, Christopher G., Hoque, Ashfaqul, Dite, Toby A., Means, Anthony R., Kemp, Bruce and Scott, John W.. (2017). Impact of genetic variation on human CaMKK2 regulation by Ca2+ -calmodulin and multisite phosphorylation. Scientific Reports. 7, pp. 1 - 11. https://doi.org/10.1038/srep43264
AMPK ß1 reduces tumor progression and improves survival in p53 null mice
Houde, Vanessa P., Donzelli, Sara, Sacconi, Andrea, Galic, Sandra, Hammill, Joanne A., Bramson, Jonathan L., Foster, Robert A., Tsakiridis, Theodoros, Kemp, Bruce, Grasso, Giuseppe, Blandino, Giovanni, Muti, Paola and Steinberg, Gregory R.. (2017). AMPK ß1 reduces tumor progression and improves survival in p53 null mice. Molecular Oncology. 11(9), pp. 1143 - 1155. https://doi.org/10.1002/1878-0261.12079
The sweet side of AMPK signaling: Regulation of GFAT1
Scott, John W. and Oakhill, Jonathan S.. (2017). The sweet side of AMPK signaling: Regulation of GFAT1. Biochemical Journal. 474(7), pp. 1289 - 1292. https://doi.org/10.1042/BCJ20170006
The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
Dite, Toby A., Ling, Naomi, Scott, John W., Hoque, Ashfaqul, Galic, Sandra, Parker, Benjamin L., Ngoei, Kevin R.W., Langendorf, Christopher G., O'Brien, Matthew, Kundu, Mondira, Viollet, Benoit, Steinberg, Gregory R., Sakamoto, Kei, Kemp, Bruce and Oakhill, Jonathan S.. (2017). The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nature Communications. 8(571), pp. 1 - 14. https://doi.org/10.1038/s41467-017-00628-y
Metabolism: Energy sensing through a sugar diphosphate
Kemp, Bruce and Oakhill, Jonathan S.. (2017). Metabolism: Energy sensing through a sugar diphosphate. Nature. 548(7665), pp. 36 - 37. https://doi.org/10.1038/nature23099
Fake inhibitors: AMPK activation trumps inhibition
Langendorf, Christopher G., Scott, John W. and Kemp, Bruce E.. (2017). Fake inhibitors: AMPK activation trumps inhibition. Cell Chemical Biology. 24(7), pp. 775 - 777. https://doi.org/10.1016/j.chembiol.2017.07.005
Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons
Bayliss, Jacqueline A., Lemus, Moyra B., Santos, Vanessa, Deo, Minh, Davies, Jeffrey S., Kemp, Bruce Ernest, Elsworth, John D. and Andrews, Zane B.. (2016). Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PLoS ONE. 11(7), pp. 1 - 15. https://doi.org/10.1371/journal.pone.0159381
Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding
Langendorf, Christopher G., Ngoei, Kevin R. W., Scott, John W., Ling, Naomi X. Y., Issa, Sam M. A., Gorman, Michael A., Parker, Michael W., Sakamoto, Kei, Oakhill, Jonathan S. and Kemp, Bruce Ernest. (2016). Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nature Communications. 7, pp. 1 - 8. https://doi.org/10.1038/ncomms10912
Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity
Annesley, Sarah J., Lay, Sui T., De Piazza, Shawn W., Sanislav, Oana, Hammersley, Eleanor, Allan, Claire Y., Francione, Lisa M., Bui, Minh Q., Chen, Zhi-Ping, Ngoei, Kevin R. W., Tassone, Flora, Kemp, Bruce E., Storey, Elsdon, Evans, Andrew, Loesch, Danuta Z. and Fisher, Paul R.. (2016). Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity. Disease Models and Mechanisms. 9(9), pp. 1295 - 1305. https://doi.org/10.1242/dmm.025684
Ghrelin-AMPK signaling mediates the neuroprotective effects of calorie restriction in Parkinson's Disease
Bayliss, Jacqueline A., Lemus, Moyra B., Stark, Romana, Santos, Vanessa V., Thompson, Aiysha, Rees, Daniel J., Galic, Sandra, Elsworth, John D., Kemp, Bruce Ernest, Davies, Jeffrey S. and Andrews, Zane B.. (2016). Ghrelin-AMPK signaling mediates the neuroprotective effects of calorie restriction in Parkinson's Disease. Journal of Neuroscience. 36(10), pp. 3049 - 3063. https://doi.org/10.1523/JNEUROSCI.4373-15.2016
The social supply of cannabis among young people in Australia
Lenton, Simon, Grigg, Jodie, Scott, John, Barratt, Monica and Eleftheriadis, Dina. (2015). The social supply of cannabis among young people in Australia. Trends and Issues in Crime and Criminal Justice. (503), pp. 1-6.
Skeletal muscle AMPK is essential for the maintenance of FNDC5 expression
Lally, James S. V., Ford, Rebecca J., Johar, Jasper, Crane, Justin D., Kemp, Bruce Ernest and Steinberg, Gregory R.. (2015). Skeletal muscle AMPK is essential for the maintenance of FNDC5 expression. Physiological Reports. 3(5), pp. 1 - 9. https://doi.org/10.14814/phy2.12343
Salicylate improves macrophage cholesterol homeostasis via activation of Ampk
Fullerton, Morgan D., Ford, Rebecca J., McGregor, Chelsea P., LeBlond, Nicholas D., Snider, Shayne A., Stypa, Stephanie A., Day, Emily A., Lhoták, Šárka, Schertzer, Jonathan D., Austin, Richard C., Kemp, Bruce Ernest and Steinberg, Gregory R.. (2015). Salicylate improves macrophage cholesterol homeostasis via activation of Ampk. Journal of Lipid Research. 56(5), pp. 1025 - 1033. https://doi.org/10.1194/jlr.M058875
Choreography of AMPK activation
Langerdorf, Christopher G. and Kemp, Bruce Ernest. (2015). Choreography of AMPK activation. Cell Research. 25(1), pp. 5 - 6. https://doi.org/10.1038/cr.2014.163
Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise
O'Neill, Hayley M., Lally, James S., Galic, Sandra, Pulinilkunnil, Thomas, Ford, Rebecca J., Dyck, Jason R. B., Van Denderen, Bryce J,, Kemp, Bruce Ernest and Steinberg, Gregory R.. (2015). Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. Physiological Reports. 3(7), pp. 1 - 10. https://doi.org/10.14814/phy2.12444
Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity
Ford, Rebecca, Fullerton, Morgan, Pinkosky, Stephen, Day, Emily, Scott, John, Oakhill, Jonathan, Bujak, Adam, Smith, Brennan, Crane, Justin, Blumer, Regje, Marcinko, Katarina, Kemp, Bruce, Gerstein, Hertzel and Steinberg, Gregory. (2015). Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochemical Journal. 468(1), pp. 125 - 132. https://doi.org/10.1042/BJ20150125
High intensity interval training improves liver and adipose tissue insulin sensitivity
Marcinko, Katarina, Sikkema, Sarah R., Samaan, M. Constantine, Kemp, Bruce Ernest, Fullerton, Morgan D. and Steinberg, Gregory R.. (2015). High intensity interval training improves liver and adipose tissue insulin sensitivity. Molecular Metabolism. 4(12), pp. 903 - 915. https://doi.org/10.1016/j.molmet.2015.09.006
Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release
Scott, John, Galic, Sandra, Graham, Kate, Foitzik, Richard, Ling, Naomi, Dite, Toby, Issa, Samah, Langendorf, Chris, Weng, Qing, Thomas, Helen, Kay, Thomas, Birnberg, Neal, Steinberg, Gregory, Kemp, Bruce and Oakhill, Jonathan. (2015). Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release. Chemistry and Biology. 22(6), pp. 705 - 711. https://doi.org/10.1016/j.chembiol.2015.05.011
AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism
Sung, Miranda M., Zordoky, Beshay N. M., Bujak, Adam L., Lally, James S. V., Fung, David, Young, Martin E., Horman, Sandrine, Miller, Edward J., Light, Peter E., Kemp, Bruce Ernest, Steinberg, Gregory R. and Dyck, Jason R. B.. (2015). AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. Cardiovascular Research. 107(2), pp. 235 - 245. https://doi.org/10.1093/cvr/cvv166
Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis
O'Brien, Andrew J., Villani, Linda A., Broadfield, Lindsay A., Houde, Vanessa P., Galic, Sandra, Blandino, Giovanni, Kemp, Bruce Ernest, Tsakiridis, Theodoros, Muti, Paola and Steinberg, Gregory R.. (2015). Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis. Biochemical Journal. 469(2), pp. 177 - 187. https://doi.org/10.1042/Bj20150122
The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice
Marcinko, Katarina, Bujak, Adam L., Lally, James S. V., Ford, Rebecca J., Wong, Tammy H., Smith, Brennan K., Kemp, Bruce Ernest, Jenkins, Yonchu, Li, Wei, Kinsella, Todd M., Hitoshi, Yasumichi and Steinberg, Gregory R.. (2015). The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice. Molecular Metabolism. 4(9), pp. 643 - 651. https://doi.org/10.1016/j.molmet.2015.06.002
AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging
Bujak, Adam L., Crane, Justin D., Lally, James S., Ford, Rebecca J., Kang, Sally J., Rebalka, Irena A., Green, Alex E., Kemp, Bruce Ernest, Hawke, Thomas J., Schertzer, Jonathan D. and Steinberg, Gregory R.. (2015). AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. Cell Metabolism. 21(6), pp. 883 - 890. https://doi.org/10.1016/j.cmet.2015.05.016
Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging
Crane, Justin D., MacNeil, Lauren G., Lally, James S. V., Ford, Rebecca J., Bujak, Adam L., Brar, Ikdip K., Kemp, Bruce Ernest, Raha, Sandeep, Steinberg, Gregory Robert and Tarnopolsky, Mark A.. (2015). Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging. Aging Cell. 14(4), pp. 625 - 634. https://doi.org/10.1111/acel.12341
Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder
Scott, John, Park, Elizabeth, Rodriguiz, Ramona, Oakhill, Jonathan, Issa, Samah, O'Brien, Matthew, Dite, Toby, Langendorf, Christopher, Wetsel, William, Means, Anthony and Kemp, Bruce. (2015). Autophosphorylation of CaMKK2 generates autonomous activity that is disrupted by a T85S mutation linked to anxiety and bipolar disorder. Scientific Reports. 5, pp. 1 - 10. https://doi.org/10.1038/srep14436
SnRK1 from Arabidopsis thaliana is an atypical AMPK
Emanuelle, Shane, Hossain, Mohammed Iqbal, Moller, Isabel E., Pedersen, Henriette L., van de Meene, Allison M. L., Doblin, Monika S., Koay, Ann, Oakhill, Jonathan S., Scott, John W., Willats, William G. T., Kemp, Bruce Ernest, Bacic, Antony, Gooley, Paul R. and Stapleton, David I.. (2015). SnRK1 from Arabidopsis thaliana is an atypical AMPK. Plant Journal. 82(2), pp. 183 - 192. https://doi.org/10.1111/tpj.12813
PPARδ Activation attenuates hepatic steatosis in Ldlr−/− mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity
Bojic, Lazar, Telford, Dawn, Fullerton, Morgan, Ford, Rebecca, Sutherland, Brian, Edwards, Jane, Sawyez, Cynthia, Gros, Robert, Kemp, Bruce, Steinberg, Gregory and Huff, Murray. (2014). PPARδ Activation attenuates hepatic steatosis in Ldlr−/− mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity. Journal of Lipid Research. 55(7), pp. 1254 - 1266. https://doi.org/10.1194/jlr.M046037
PPARδ activation attenuates hepatic steatosis in Ldlr−/− mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity
Bojic, Lazar A., Telford, Dawn E., Fullerton, Morgan D., Ford, Rebecca J., Sutherland, Brian G., Edwards, Jane Y., Sawyez, Cynthia G., Gros, Robert, Kemp, Bruce Ernest, Steinberg, Gregory R. and Huff, Murray W.. (2014). PPARδ activation attenuates hepatic steatosis in Ldlr−/− mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity. Journal of Lipid Research. 55(7), pp. 1254 - 1266. https://doi.org/10.1194/jlr.M046037
Muscle-specific AMPK ß1ß2-null mice display a myopathy due to loss of capillary density in nonpostural muscles
Thomas, Melissa, Wang, David, D'Souza, Donna, Krause, Matthew, Layne, Andrew, Criswell, David, O'Neill, Hayley, Connor, Michael, Anderson, Judy, Kemp, Bruce, Steinberg, Gregory and Hawke, Thomas. (2014). Muscle-specific AMPK ß1ß2-null mice display a myopathy due to loss of capillary density in nonpostural muscles. The FASEB Journal. 28(5), pp. 2098 - 2107. https://doi.org/10.1096/fj.13-238972
Evidence for the role of AMPK in regulating PGC-1 alpha expression and mitochondrial proteins in mouse epididymal adipose tissue
Wan, Zhongxiao, Root-Mccaig, Jared, Castellani, Laura, Kemp, Bruce, Steinberg, Gregory and Wright, David. (2014). Evidence for the role of AMPK in regulating PGC-1 alpha expression and mitochondrial proteins in mouse epididymal adipose tissue. Obesity: a resourch journal. 22(3), pp. 730 - 738. https://doi.org/10.1002/oby.20605
Activation of AMPK reduces the co-transporter activity of NKCC1
Fraser, Scott A., Davies, Matthew R. P., Katerelos, Marina, Gleich, Kurt, Choy, Suet-Wan, Steel, Rohan, Galic, Sandra, Mount, Peter F., Kemp, Bruce Ernest and Power, David A.. (2014). Activation of AMPK reduces the co-transporter activity of NKCC1. Molecular Membrane Biology. 31(2-3), pp. 95 - 102. https://doi.org/10.3109/09687688.2014.902128
Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models
Perera, Nirma, Sheean, Rebecca, Scott, John, Kemp, Bruce, Horne, Malcolm and Turner, Bradley. (2014). Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models. PLoS One (online). 9(3), pp. 1 - 11. https://doi.org/10.1371/journal.pone.0090449
Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance
Bujak, Adam, Blumer, Regje, Marcinko, Katarina, Fullerton, Morgan, Kemp, Bruce and Steinberg, Gregory. (2014). Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance. Journal of Applied Physiology. 117(2), pp. 171 - 179. https://doi.org/10.1152/japplphysiol.01101.2013
Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress
McGee, Sean, Swinton, Courtney, Morrison, Shona, Gaur, Vidhi, Campbell, Duncan, Jorgensen, Sebastian, Kemp, Bruce, Baar, Keith, Steinberg, Gregory and Hargreaves, Mark. (2014). Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress. The FASEB Journal. 28(8), pp. 3384 - 3395. https://doi.org/10.1096/fj.14-249359
ATP sensitive bi-quinoline activator of the AMP-activated protein kinase
Scott, John, Oakhill, Jonathan, Ling, Naomi, Langendorf, Christopher, Foitzik, Richard, Kemp, Bruce and Issinger, Olaf-Georg. (2014). ATP sensitive bi-quinoline activator of the AMP-activated protein kinase. Biochemical and Biophysical Research Communications. 443(2), pp. 435 - 440. https://doi.org/10.1016/j.bbrc.2013.11.130
Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662
Ducommun, Serge, Ford, Rebecca J., Bultot, Laurent, Deak, Maria, Bertrand, Luc, Kemp, Bruce Ernest, Steinberg, Gregory R. and Sakamoto, Kei. (2014). Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662. American Journal of Physiology - Endocrinology and Metabolism. 306(6), pp. 688 - 696. https://doi.org/10.1152/ajpendo.00672.2013
Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling
Scott, John, Ling, Naomi, Issa, Samah, Dite, Toby, O'Brien, Matthew, Chen, Zhi-Ping, Galic, Sandra, Langendorf, Christopher, Steinberg, Gregory, Kemp, Bruce and Oakhill, Jonathan. (2014). Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chemistry and Biology. 21(5), pp. 619 - 627. https://doi.org/10.1016/j.chembiol.2014.03.006
Novel mechanisms of Na+ retention in obesity: Phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK
Davies, Matthew R. P., Fraser, Scott A., Galic, Sandra, Choy, Suet-Wan, Katerelos, Marina, Gleich, Kurt, Kemp, Bruce Ernest, Mount, Peter F. and Power, David A.. (2014). Novel mechanisms of Na+ retention in obesity: Phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK. American Journal of Physiology - Renal Physiology. 307(1), pp. 96 - 106. https://doi.org/10.1152/ajprenal.00524.2013
Mechanism of action of compound-13 : An a1-selective small molecule activator of AMPK
Hunter, Roger, Foretz, Marc, Bultot, Laurent, Fullerton, Morgan, Deak, Maria, Ross, Fiona, Hawley, Simon, Shpiro, Natalia, Viollet, Benoit, Barron, Denis, Kemp, Bruce, Steinberg, Gregory, Hardie, David Grahame and Sakamoto, Kei. (2014). Mechanism of action of compound-13 : An a1-selective small molecule activator of AMPK. Chemistry and Biology. 21(7), pp. 866 - 879. https://doi.org/10.1016/j.chembiol.2014.05.014
Differences between first episode schizophrenia and schizoaffective disorder
Cotton, Sue, Lambert, M, Schimmelmann, B, Mackinnon, Andrew, Gleeson, John, Berk, Michael, Hides, L, Chanen, Andrew, Scott, J and Schottle, D. (2013). Differences between first episode schizophrenia and schizoaffective disorder. Schizophrenia Research. https://doi.org/10.1016/j.schres.2013.02.036
Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin
Fullerton, Morgan, Galic, Sandra, Marcinko, Katarina, Sikkema, Sarah, Pulinilkunnil, Thomas, Chen, Zhi-Ping, O'Neill, Hayley, Ford, Rebecca, Palanivel, Rengasamy, O'Brien, Matthew, Hardie, D. Grahame, Macaulay, Lance, Schertzer, Jonathan, Dyck, Jason, van Denderen, Bryce, Kemp, Bruce and Steinberg, Gregory. (2013). Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine. 19(12), pp. 1649 - 1654. https://doi.org/10.1038/nm.3372
AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice
O’Neill, Hayley M., Lally, James S., Galic, Sandra, Thomas, Melissa, Azizi, Paymon D., Fullerton, Morgan D., Smith, Brennan K., Pulinilkunnil, Thomas, Chen, Zhiping, Constantine Samaan, M., Jorgensen, Sebastian B., Dyck, Jason R. B., Holloway, Graham P., Hawke, Thomas J., van Denderen, Bryce J., Kemp, Bruce E. and Steinberg, Gregory R.. (2012). AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia. 57(8), pp. 1693 - 1702. https://doi.org/10.1007/s00125-014-3273-1
AMPK-dependent inhibitory phosphorylation of ACC is not essential for maintaining myocardial fatty acid oxidation
Zordoky, Beshay N.M., Nagendran, Jeevan, Pulinilkunnil, Thomas, Kienesberger, Petra C., Masson, Grant, Waller, Terri J., Kemp, Bruce E., Steinberg, Gregory R. and Dyck, Jason R. B.. (2012). AMPK-dependent inhibitory phosphorylation of ACC is not essential for maintaining myocardial fatty acid oxidation. Circulation Research. 115(5), pp. 518 - 524. https://doi.org/10.1161/CIRCRESAHA.115.304538
The ancient drug salicylate directly activates AMP-activated protein kinase
Hawley, Simon, Fullerton, Morgan, Ross, Fiona, Schertzer, Jonathan, Chevtzoff, Cyrille, Walker, Katherine, Peggie, Mark, Zibrova, Darya, Green, Kevin, Mustard, Kirsty, Kemp, Bruce, Sakamoto, Kei, Steinberg, Gregory and Hardie, D. Grahame. (2012). The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 336(6083), pp. 918 - 922. https://doi.org/10.1126/science.1215327
Pro-GRP-derived peptides are expressed in colorectal cancer cells and tumors and are biologically active in vivo
Patel, Oneel, Clyde, Daniel, Chang, Mike, Nordlund, Marianne, Steel, Rohan, Kemp, Bruce, Pritchard, D. Mark, Shulkes, Arthur and Baldwin, Graham. (2012). Pro-GRP-derived peptides are expressed in colorectal cancer cells and tumors and are biologically active in vivo. Endocrinology. 153(3), pp. 1082 - 1092. https://doi.org/10.1210/en.2011-1875
The outcome of renal ischemia-reperfusion injury is unchanged in AMPK-ß1 deficient mice
Mount, Peter, Gleich, Kurt, Tam, Shanna, Fraser, Scott, Choy, Suet-Wan, Dwyer, Karen, Lu, Bo, Van Denderen, Bryce, Fingerle-Rowson, Gunter, Bucala, Richard, Kemp, Bruce and Power, David. (2012). The outcome of renal ischemia-reperfusion injury is unchanged in AMPK-ß1 deficient mice. PLoS One (online). 7(1), pp. 1 - 10. https://doi.org/10.1371/journal.pone.0029887
Inhibition of the heterotetrameric K+ channel KCNQ1/KCNE1 by the AMP-activated protein kinase
Alesultan, Ioana, Foller, Michael, Sopjani, Mentor, Dermaku-Sopjani, Miribane, Zelenak, Christine, Frohlich, Henning, Velic, Ana, Fraser, Scott, Kemp, Bruce, Seebohm, Guiscard, Volkl, Harald and Lang, Florian. (2011). Inhibition of the heterotetrameric K+ channel KCNQ1/KCNE1 by the AMP-activated protein kinase. Molecular Membrane Biology. 28(2), pp. 79 - 89. https://doi.org/10.3109/09687688.2010.520037
AMP-activated protein kinase (AMPK) ß1ß2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise
O'Neill, Hayley M., Maarbjerg, Stine J., Crane, Justin D., Jeppesen, Jacob, Jorgensen, Sebastian B., Schertzer, Jonathan D., Shyroka, Olga, Kiens, Bente, Van Denderen, Bryce J., Tarnopolsky, Mark A., Kemp, Bruce Ernest, Richter, Erik A. and Steinberg, Gregory R.. (2011). AMP-activated protein kinase (AMPK) ß1ß2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proceedings of the National Academy of Sciences of USA. 108(38), pp. 16092 - 16097. https://doi.org/10.1073/pnas.1105062108
Ca 2+/calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation
Green, Michelle, Scott, John, Steel, Rohan, Oakhill, Jonathan, Kemp, Bruce and Means, Anthony. (2011). Ca 2+/calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation. Journal of Biological Chemistry. 286(32), pp. 28066 - 28079. https://doi.org/10.1074/jbc.M111.251504
Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan, Schertzer, Jonathan, Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl, Izon, David, Honeyman, Jane, Chen, Zhi-Ping, Van Denderen, Bryce, Kemp, Bruce and Steinberg, Gregory. (2011). Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577
Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan D., Schertzer, Jonathan D., Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl R., Izon, David, Honeyman, Jane, Chen, Zhi-Ping, van Denderen, Bryce J., Kemp, Bruce Ernest and Steinberg, Gregory R.. (2011). Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577
Inhibition of Kir2.1 (KCNJ2) by the AMP-activated protein kinase
Alesutan, Ioana, Munoz, Carlos, Sopjani, Mentor, Dermaku-Sopjani, Miribane, Michael, Diana, Fraser, Scott, Kemp, Bruce, Seebohm, Guiscard, Foller, Michael and Lang, Florian. (2011). Inhibition of Kir2.1 (KCNJ2) by the AMP-activated protein kinase. Biochemical and Biophysical Research Communications. 408(4), pp. 505 - 510. https://doi.org/10.1016/j.bbrc.2011.04.015
Inhibition of Connexin 26 by the AMP-activated protein kinase
Alesutan, Ioana, Sopjani, Mentor, Munoz, Carlos, Fraser, Scott, Kemp, Bruce, Foller, Michael and Lang, Florian. (2011). Inhibition of Connexin 26 by the AMP-activated protein kinase. Journal of Membrane Biology: an international journal for studies on the structure, function and genesis of biomembranes. 240(3), pp. 151 - 158. https://doi.org/10.1007/s00232-011-9353-y
AMPK is a direct adenylate charge-regulated protein kinase
Oakhill, Jonathan S., Steel, Rohan, Chen, Zhi-Ping, Scott, John W., Ling, Naomi, Tam, Shanna and Kemp, Bruce Ernest. (2011). AMPK is a direct adenylate charge-regulated protein kinase. Science. 332(6036), pp. 1433 - 1435. https://doi.org/10.1126/science.1200094
AMPK couples plasma renin to cellular metabolism by phosphorylation of ACC1
Fraser, Scott A., Choy, Suet-Wan, Pastor-Soler, Núria M., Li, Hui, Davies, Matthew R. P., Cook, Natasha, Katerelos, Marina, Mount, Peter F., Gleich, Kurt, McRae, Jennifer L., Dwyer, Karen M., van Denderen, Bryce J. W., Hallows, Kenneth R., Kemp, Bruce E. and Power, David A.. (2010). AMPK couples plasma renin to cellular metabolism by phosphorylation of ACC1. American Journal of Physiology - Renal Physiology. 305(5), pp. F679 - F690. https://doi.org/10.1152/ajprenal.00407.2012
Impaired skeletal muscle beta-adrenergic activation and lipolysis are associated with whole-body insulin resistance in rats bred for low intrinsic exercise capacity
Lessard, Sarah J., Rivas, Donato A., Chen, Zhu-Ping, van Denderen, Bryce J., Watt, Matthew J., Koch, Lauren G., Britton, Steven L., Kemp, Bruce Ernest and Hawley, John Alan. (2009). Impaired skeletal muscle beta-adrenergic activation and lipolysis are associated with whole-body insulin resistance in rats bred for low intrinsic exercise capacity. Endocrinology. 150(11), pp. 4883 - 4891. https://doi.org/10.1210/en.2009-0158
Fat adaptation followed by carbohydrate restoration increases AMPK activity in skeletal muscle from trained humans
Yeo, Wee Kian, Lessard, Sarah J., Chen, Zhi-Ping, Garnham, Andrew P., Burke, Louise, Rivas, Donato A., Kemp, Bruce Ernest and Hawley, John Alan. (2008). Fat adaptation followed by carbohydrate restoration increases AMPK activity in skeletal muscle from trained humans. Journal of Applied Physiology. 105(5), pp. 1519 - 1526. https://doi.org/10.1152/japplphysiol.90540.2008
Activation of AMPK reduces the co-transporter activity of NKCC1
Fraser, Scott A., Davies, Matthew, Katerelos, Marina, Gleich, Kurt, Choy, Suet-Wan, Steel, Rohan, Galic, Sandra, Mount, Peter F., Kemp, Bruce E. and Power, David A.. (1999). Activation of AMPK reduces the co-transporter activity of NKCC1. Molecular Membrane Biology. 31(2-3), pp. 95 - 102. https://doi.org/10.3109/09687688.2014.902128
Myosin light chain kinases
Kemp, Bruce E. and Stull, James T.. (1990). Myosin light chain kinases. In In B. E. Kemp (Ed.). Peptides and Protein Phosphorylation pp. 115 - 133 CRC Press. https://doi.org/10.1201/9781351075442