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
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