KSR2 Is an Essential Regulator of AMP Kinase, Energy Expenditure, and Insulin Sensitivity

Diane L. Costanzo-Garvey, Paul T. Pfluger, Michele K. Dougherty, Jeffery L. Stock, Matthew Boehm, Oleg Chaika, Mario R. Fernandez, Kurt Fisher, Robert L. Kortum, Eun Gyoung Hong, John Y. Jun, Hwi Jin Ko, Aimee Schreiner, Deanna J. Volle, Tina Treece, Amy L. Swift, Mike Winer, Denise Chen, Min Wu, Lisa R. LeonAndrey S. Shaw, John McNeish, Jason K. Kim, Deborah K. Morrison, Matthias H. Tschöp, Robert E. Lewis

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

Kinase suppressors of Ras 1 and 2 (KSR1 and KSR2) function as molecular scaffolds to potently regulate the MAP kinases ERK1/2 and affect multiple cell fates. Here we show that KSR2 interacts with and modulates the activity of AMPK. KSR2 regulates AMPK-dependent glucose uptake and fatty acid oxidation in mouse embryonic fibroblasts and glycolysis in a neuronal cell line. Disruption of KSR2 in vivo impairs AMPK-regulated processes affecting fatty acid oxidation and thermogenesis to cause obesity. Despite their increased adiposity, ksr2-/- mice are hypophagic and hyperactive but expend less energy than wild-type mice. In addition, hyperinsulinemic-euglycemic clamp studies reveal that ksr2-/- mice are profoundly insulin resistant. The expression of genes mediating oxidative phosphorylation is also downregulated in the adipose tissue of ksr2-/- mice. These data demonstrate that ksr2-/- mice are highly efficient in conserving energy, revealing a novel role for KSR2 in AMPK-mediated regulation of energy metabolism.

Original languageEnglish (US)
Pages (from-to)366-378
Number of pages13
JournalCell Metabolism
Volume10
Issue number5
DOIs
StatePublished - Nov 4 2009

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Costanzo-Garvey, D. L., Pfluger, P. T., Dougherty, M. K., Stock, J. L., Boehm, M., Chaika, O., Fernandez, M. R., Fisher, K., Kortum, R. L., Hong, E. G., Jun, J. Y., Ko, H. J., Schreiner, A., Volle, D. J., Treece, T., Swift, A. L., Winer, M., Chen, D., Wu, M., ... Lewis, R. E. (2009). KSR2 Is an Essential Regulator of AMP Kinase, Energy Expenditure, and Insulin Sensitivity. Cell Metabolism, 10(5), 366-378. https://doi.org/10.1016/j.cmet.2009.09.010