AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol

Journal article

Hoffman, Nolan John, Habegger, Kirk M., Ridenour, Colin M., Broznick, Joseph T. and Elmendon, Jeffrey S.. (2012). AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol. Endocrinology. 153(5), pp. 2130 - 2141. https://doi.org/10.1210/en.2011-2099
AuthorsHoffman, Nolan John, Habegger, Kirk M., Ridenour, Colin M., Broznick, Joseph T. and Elmendon, Jeffrey S.
Abstract

AMP-activated protein kinase (AMPK) enhances glucose transporter GLUT4 regulation. AMPK also suppresses energy-consuming pathways such as cholesterol synthesis. Interestingly, recent in vitro and in vivo data suggest that excess membrane cholesterol impairs GLUT4 regulation. Therefore, this study tested whether a beneficial, GLUT4-regulatory aspect of AMPK stimulation involved cholesterol lowering. Using L6 myotubes stably expressing an exofacial myc-epitope-tagged-GLUT4, AMPK stimulation by 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR; 45 min, 1 mM) or 2,4-dinitrophenol (DNP; 30 min, 200 μM) increased cell surface GLUT4myc labeling by approximately ∼25% (P < 0.05). Insulin (20 min, 100 nM) also increased GLUT4myc labeling by about 50% (P < 0.05), which was further enhanced (∼25%, P < 0.05) by AICAR or DNP. Consistent with AMPK-mediated suppression of cholesterol synthesis, AICAR and DNP decreased membrane cholesterol by 20–25% (P < 0.05). Whereas AMPK knockdown prevented the enhanced basal and insulin-stimulated GLUT4myc labeling by AICAR and DNP, cholesterol replenishment only blocked the AMPK-associated enhancement in insulin action. Cells cultured in a hyperinsulinemic milieu, resembling conditions in vivo that promote the progression/worsening of insulin resistance, displayed an increase in membrane cholesterol. This occurred concomitantly with a loss of cortical filamentous actin (F-actin) and defects in GLUT4 regulation by insulin. These derangements were prevented by AMPK stimulation. Examination of skeletal muscle from insulin-resistant Zucker rats revealed a similar elevation in membrane cholesterol and loss of F-actin. Lowering cholesterol to control levels restored F-actin structure and insulin sensitivity. In conclusion, these data suggest a novel aspect of GLUT4 regulation by AMPK involves membrane cholesterol lowering. Moreover, this AMPK-mediated process protected against hyperinsulinemia-induced insulin resistance.

Keywordsactins; cholesterol; hyperinsulinism; tissue membrane; skeletal muscles; insulin; ampk; skeletal myocytes; aica ribonucleotide
Year2012
JournalEndocrinology
Journal citation153 (5), pp. 2130 - 2141
PublisherThe Endocrine Society
ISSN0013-7227
Digital Object Identifier (DOI)https://doi.org/10.1210/en.2011-2099
Scopus EID2-s2.0-84860339683
Page range2130 - 2141
Research GroupMary MacKillop Institute for Health Research
Publisher's version
File Access Level
Controlled
Place of publicationUnited States
Permalink -

https://acuresearchbank.acu.edu.au/item/89yz8/ampk-enhances-insulin-stimulated-glut4-regulation-via-lowering-membrane-cholesterol

Log in to edit

Restricted files

Publisher's version

  • 127
    total views
  • 0
    total downloads
  • 4
    views this month
  • 0
    downloads this month
These values are for the period from 19th October 2020, when this repository was created.

Export as

Related outputs

Exercise-regulated mitochondrial and nuclear signalling networks in skeletal muscle
Reisman, Elizabeth G., Hawley, John A. and Hoffman, Nolan J.. (2024). Exercise-regulated mitochondrial and nuclear signalling networks in skeletal muscle. Sports Medicine. 54, pp. 1097-1119. https://doi.org/10.1007/s40279-024-02007-2
Discordant skeletal muscle gene and protein responses to exercise
Bishop, David J., Hoffman, Nolan J., Taylor, Dale F., Saner, Nicholas J., Lee, Matthew J.-C. and Hawley, John A.. (2023). Discordant skeletal muscle gene and protein responses to exercise. Trends in Biochemical Sciences. 48(11), pp. 927-936. https://doi.org/10.1016/j.tibs.2023.08.005
Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator
Ovens, Ashley J., Gee, Yi Sing, Ling, Naomi X. Y., Yu, Dingyi, Hardee, Justin P., Chung, Jin D., Ngoei, Kevin R. W., Waters, Nicholas J., Hoffman, Nolan J., Scott, John W., Loh, Kim, Spengler, Katrin, Heller, Regine, Parker, Michael W., Lynch, Gordon S., Huang, Fei, Galic, Sandra, Kemp, Bruce E., Baell, Jonathan B., ... Langendorf, Christopher G.. (2022). Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator. Biochemical Journal. 479(11), pp. 1181-1204. https://doi.org/10.1042/BCJ20220067
Disrupting AMPK-glycogen binding in mice increases carbohydrate utilization and reduces exercise capacity
Janzen, Natalie R., Whitfield, Jamie, Murray-Segal, Lisa, Kemp, Bruce E., Hawley, John A. and Hoffman, Nolan J.. (2022). Disrupting AMPK-glycogen binding in mice increases carbohydrate utilization and reduces exercise capacity. Frontiers in Physiology. 13, p. 859246. https://doi.org/10.3389/fphys.2022.859246
Metabolomics reveals mouse plasma metabolite responses to acute exercise and effects of disrupting AMPK-glycogen interactions
Belhaj, Mehdi, Lawler, Nathan, Hawley, John Alan, Broadhurst, David, Hoffman, Nolan John and Reinke, Stacey. (2022). Metabolomics reveals mouse plasma metabolite responses to acute exercise and effects of disrupting AMPK-glycogen interactions. Frontiers in Molecular Biosciences. pp. 1-16. https://doi.org/10.3389/fmolb.2022.957549
Metabolomics and lipidomics : Expanding the molecular landscape of exercise biology
Belhaj, Mehdi R., Lawler, Nathan G. and Hoffman, Nolan J.. (2021). Metabolomics and lipidomics : Expanding the molecular landscape of exercise biology. Metabolites. 11(151), p. Article 151. https://doi.org/10.3390/metabo11030151
Mice with whole-body disruption of AMPK-glycogen binding have increased adiposity, reduced fat oxidation and altered tissue glycogen dynamics
Janzen, Natalie, Whitfield, Jamie, Murray-Segal, Lisa, Kemp, Bruce E., Hawley, John A. and Hoffman, Nolan J.. (2021). Mice with whole-body disruption of AMPK-glycogen binding have increased adiposity, reduced fat oxidation and altered tissue glycogen dynamics. International Journal of Molecular Sciences. 22(17), p. Article: 9616. https://doi.org/10.3390/ijms22179616
PhosR enables processing and functional analysis of phosphoproteomic data
Kim, Hani Jieun, Kim, Taiyun, Hoffman, Nolan J., Xiao, Di, James, David E., Humphrey, Sean J. and Yang, Pengyi. (2021). PhosR enables processing and functional analysis of phosphoproteomic data. Cell Reports. 34, p. 108771. https://doi.org/10.1101/2020.08.31.276329
Omega-3 polyunsaturated fatty acids mitigate palmitate-induced impairments in skeletal muscle cell viability and differentiation
Tachtsis, Bill, Whitfield, Jamie, Hawley, John A. and Hoffman, Nolan J.. (2020). Omega-3 polyunsaturated fatty acids mitigate palmitate-induced impairments in skeletal muscle cell viability and differentiation. Frontiers in Physiology. 11, pp. 1-13. https://doi.org/10.3389/fphys.2020.00563
Genetic loss of AMPK-glycogen binding destabilizes AMPK and disrupts metabolism
Hoffman, Nolan J., Whitfield, Jamie, Janzen, Natalie R., Belhaj, Mehdi R., Galic, Sandra, Murray-Segal, Lisa, Smiles, William J., Ling, Naomi X. Y., Dite, Toby A., Scott, John W., Oakhill, Jonathan S., Brink, Robert, Kemp, Bruce E. and Hawley, John A.. (2020). Genetic loss of AMPK-glycogen binding destabilizes AMPK and disrupts metabolism. Molecular Metabolism. 41, pp. 1-13. https://doi.org/10.1016/j.molmet.2020.101048
Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry
Nelson, Marin E., Parker, Benjamin L., Burchfield, James G., Hoffman, Nolan J., Needham, Elise J., Cooke, Kristen C., Naim, Timur, Sylow, Lykke, Ling, Naomi X. Y., Francis, Deanne, Norris, Dougall M., Chaudhuri, Rima, Oakhill, Jonathan S., Richter, Erik A., Lynch, Gordon S., Stockli, Jacqueline and James, David E.. (2019). Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry. The EMBO Journal. 38(24), pp. 1 - 20. https://doi.org/10.15252/embj.2019102578
High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice
Burchfield, James G., Kebede, Melkam A., Meoli, Christopher C., Stockli, Jacqueline, Whitworth, P. Tess, Wright, Amanda L., Hoffman, Nolan John, Minard, Annabel Y., Ma, Xiuquan, Krycer, James R., Nelson, Marin E., Tan, Shi-Xlong, Yau, Belinda, Thomas, Kristen C., Wee, Natalie K.Y., Khor, Ee-Cheng, Enriquez, Ronaldo F., Vissel, Bryce, Biden, Trevor J., ... Fazakerley, Daniel J.. (2018). High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice. Journal of Biological Chemistry. 293(15), pp. 5731 - 5745. https://doi.org/10.1074/jbc.RA117.000808
Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance
Fazakerley, Daniel J., Chaudhuri, Rima, Yang, Pengyi, Maghzal, Ghassan J., Thomas, Kristen C., Krycer, James R., Humphrey, Sean J., Parker, Benjamin, Fisher-Wellman, Kelsey H., Meoli, Christopher C., Hoffman, Nolan, Diskin, Ciana, Burchfield, James G., Cowley, Mark J., Kaplan, Warren, Modrusan, Zora, Kolumam, Ganesh, Yang, Jean Y. H., Chen, Daniel L., ... James, David E.. (2018). Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance. eLife. 7, pp. 1 - 38. https://doi.org/10.7554/eLife.32111
Interactive roles for AMPK and glycogen from cellular energy sensing to exercise metabolism
Janzen, Natalie, Whitfield, Jamie and Hoffman, Nolan. (2018). Interactive roles for AMPK and glycogen from cellular energy sensing to exercise metabolism. International Journal of Molecular Sciences. 19(11), pp. 1 - 18. https://doi.org/10.3390/ijms19113344
High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans
Leckey, Jill J., Hoffman, Nolan J., Parr, Evelyn B., Devlin, Brooke L., Trewin, Adam J., Stepto, Nigel K., Morton, James P., Burke, Louise M. and Hawley, John A.. (2018). High dietary fat intake increases fat oxidation and reduces skeletal muscle mitochondrial respiration in trained humans. FASEB Journal. 32(6), pp. 2979-2991. https://doi.org/10.1096/fj.201700993R
Metabolomic analysis of insulin resistance across different mouse strains and diets
Stockli, Jacqueline, Fisher-Wellman, Kelsey H., Chaudhuri, Rima, Zeng, Xiao-Yi, Fazakerley, Daniel J., Meoli, Christopher C., Thomas, Kristen C., Hoffman, Nolan, Mangiafico, Salvatore P., Xirouchaki, Chrysovalantou E., Yang, Chieh H., Ilkayeva, Olga, Wong, Kari, Cooney, Gregory J., Andrikopoulos, Sofianos, Muoio, Deborah M. and James, David E.. (2017). Metabolomic analysis of insulin resistance across different mouse strains and diets. Journal of Biological Chemistry. 292(47), pp. 19135 - 19145. https://doi.org/10.1074/jbc.M117.818351
Omics and exercise : Global approaches for mapping exercise biological networks
Hoffman, Nolan John. (2017). Omics and exercise : Global approaches for mapping exercise biological networks. Cold Spring Harbor Perspectives in Medicine. 7(10), pp. 1-17. https://doi.org/10.1101/cshperspect.a029884
mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3
Kleinert, Maximilian, Parker, Benjamin L., Chaudhuri, Rima, Fazakerley, Daniel J., Serup, Annette, Thomas, Kristen C., Krycer, James R., Sylow, Lykke, Fritzen, Andreas M., Hoffman, Nolan John, Jeppesen, Jacob, Schjerling, Peter, Ruegg, Markus A., Kiens, Bente, James, David E. and Richter, Erik A.. (2016). mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3. Molecular Metabolism. 5(8), pp. 646 - 655. https://doi.org/10.1016/j.molmet.2016.06.007
Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle
Lee-Young, Robert S., Hoffman, Nolan John, Murphy, Kate T., Henstridge, Darren C., Samocha-Bonet, Dorit, Siebel, Andrew L., Iliades, Peter, Zivanovic, Borivoj, Hong, Yet H., Colgan, Timothy D., Kraakman, Michael J., Bruce, Clinton R., Gregorevic, Paul, McConell, Glenn K., Lynch, Gordon S., Drummond, Grant R., Kingwell, Bronwyn A., Greenfield, Jerry R. and Febbraio, Mark A.. (2016). Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle. Molecular Metabolism. 5(11), pp. 1083 - 1091. https://doi.org/10.1016/j.molmet.2016.09.002
Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates
Hoffman, Nolan John, Parker, Benjamin L., Chaudhuri, Rima, Fisher-Wellman, Kelsey H., Kleinert, Maximilian, Humphrey, Sean J., Yang, Pengyi, Holliday, Mira, Trefely, Sophie, Fazakerley, Daniel J., Stöckli, Jacqueline, Burchfield, James G., Jensen, Thomas E., Jothi, Raja, Kiens, Bente, Wojtaszewski, Jørgen F. P., Richter, Erik A. and James, David E.. (2015). Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metabolism. 22(5), pp. 922 - 935. https://doi.org/10.1016/j.cmet.2015.09.001
Dataset from the global phosphoproteomic mapping of early mitotic exit in human cells
Rogers, Samuel, McLoy, Rachel A., Parker, Benjamin L., Chaudhuri, Rima, Gayevskiy, Velimir, Hoffman, Nolan John, Watkins, D. Neil, Daly, Roger J., James, David E. and Burgess, Andrew. (2015). Dataset from the global phosphoproteomic mapping of early mitotic exit in human cells. Data in Brief. 5, pp. 45 - 52. https://doi.org/10.1016/j.dib.2015.08.010
The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle
Stockli, Jacqueline, Meoli, Christopher C., Hoffman, Nolan John, Fazakerley, Daniel J., Pant, Himani, Cleasby, Mark E., Ma, Xiuquan, Kleinert, Maximilian, Brandon, Amanda E., Lopez, Jamie A., Cooney, Gregory J. and James, David E.. (2015). The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle. Diabetes. 64(6), pp. 1914 - 1922. https://doi.org/10.2337/db13-1489
Global phosphoproteomic mapping of early mitotic exit in human cells identifies novel substrate dephosphorylation motifs
McLoy, Rachael A., Parker, Benjamin L., Rogers, Samuel, Chaudhuri, Rima, Gayevskiy, Velimir, Hoffman, Nolan John, Ali, Naveid, Watkins, D. Neil, Daly, Roger J., James, David E., Lorca, Thierry, Castro, Anna and Burgess, Andrew. (2015). Global phosphoproteomic mapping of early mitotic exit in human cells identifies novel substrate dephosphorylation motifs. Molecular and Cellular Proteomics. 14(8), pp. 2194 - 2212. https://doi.org/10.1074/mcp.M114.046938
PhosphOrtholog: A web-based tool for cross-species mapping of orthologous protein post-translational modifications
Chaudhuri, Rima, Sadrieh, Arash, Hoffman, Nolan J., Parker, Benjamin L., Humphrey, Sean J., Stockli, Jacqueline, Hill, Adam P., James, David E. and Yang, Jean Yee Hwa. (2015). PhosphOrtholog: A web-based tool for cross-species mapping of orthologous protein post-translational modifications. BMC Genomics. 16(617), pp. 1 - 14. https://doi.org/10.1186/s12864-015-1820-x
Structural basis for phosphorylation and lysine acetylation cross-talk in a kinase motif associated with myocardial ischemia and cardioprotection
Parker, Benjamin L., Shepherd, Nicholas E., Trefely, Sophie, Hoffman, Nolan John, White, Melanie Y., Engholm-Keller, Kasper, Hambly, Brett D., Larsen, Martin R., James, David E. and Cordwell, Stuart J.. (2014). Structural basis for phosphorylation and lysine acetylation cross-talk in a kinase motif associated with myocardial ischemia and cardioprotection. Journal of Biological Chemistry. 289(37), pp. 25890 - 25906. https://doi.org/10.1074/jbc.M114.556035
Grb10 deletion enhances muscle cell proliferation, differentiation and GLUT4 plasma membrane translocation
Mokbel, Nancy, Hoffman, Nolan John, Girgis, Christian M., Small, Lewin, Turner, Nigel, Daly, Roger J., Cooney, Gregory J. and Holt, Lowenna J.. (2014). Grb10 deletion enhances muscle cell proliferation, differentiation and GLUT4 plasma membrane translocation. Journal of Cellular Physiology. 229(11), pp. 1753 - 1764. https://doi.org/10.1002/jcp.24628
Structural basis for phosphorylation and lysine acetylation crosstalk in a kinase motif associated with myocardial ischemia and cardioprotection
Parker, Benjamin L., Shepherd, Nicholas E., Trefely, Sophie, Hoffman, Nolan John, White, Melanie Y., Engholm-Keller, Kasper, Hambly, Brett D., Larsen, Martin R., James, David E. and Cordwell, Stuart J.. (2014). Structural basis for phosphorylation and lysine acetylation crosstalk in a kinase motif associated with myocardial ischemia and cardioprotection. Journal of Biological Chemistry. 289(37), pp. 25890 - 25906. https://doi.org/10.1074/jbc.M114.556035
Transient silencing of a type IV P-type ATpase results in decreased GLUT4 translocation and altered signaling of MAPK and PI3K pathways
Hurst, Sarah, Hoffman, Nolan, Elmendorf, Jeffrey and Dhar, Madhu. (2014). Transient silencing of a type IV P-type ATpase results in decreased GLUT4 translocation and altered signaling of MAPK and PI3K pathways. In Obesity Epidemic pp. 1 - 21 CreateSpace Independent Publishing Platform.
Chromium enhances insulin responsiveness via AMPK
Hoffman, Nolan John, Penque, Brent A., Habegger, Kirk M., Sealls, Whitney, Tackett, Lixuan and Elmendorf, Jeffrey S.. (2014). Chromium enhances insulin responsiveness via AMPK. Journal of Nutritional Biochemistry. 25(5), pp. 565 - 572. https://doi.org/10.1016/j.jnutbio.2014.01.007
Ceramide accumulation in L6 skeletal muscle cells due to increased activity of ceramide synthase isoforms has opposing effects on insulin action to those caused by palmitate treatment
Frangioudakis, Georgia, Diakanastasis, Barbara, Liao, Bing-Qing M., Saville, Jennifer T., Hoffman, Nolan John, Mitchell, Todd W. and Schmitz-Peiffer, Carsten. (2013). Ceramide accumulation in L6 skeletal muscle cells due to increased activity of ceramide synthase isoforms has opposing effects on insulin action to those caused by palmitate treatment. Diabetologia. 56(12), pp. 2697 - 2701. https://doi.org/10.1007/s00125-013-3035-5
Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis
Hoffman, Nolan John and Elmendorf, Jeffrey S.. (2011). Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis. Trends in Endocrinology and Metabolism. 22(3), pp. 110 - 116. https://doi.org/10.1016/j.tem.2010.12.001