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

  1. Author:
    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.

  2. Author Address

    Costanzo-Garvey, Diane L.; Boehm, Matthew, Chaika, Oleg, Fernandez, Mario R.; Fisher, Kurt, Kortum, Robert L.; Schreiner, Aimee, Volle, Deanna J.; Treece, Tina, Lewis, Robert E.] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Pfluger, Paul T.; Tschoep, Matthias H.] Univ Cincinnati, Dept Med, Obes Res Ctr, Cincinnati, OH 45237 USA. [Dougherty, Michele K.; Morrison, Deborah K.] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Stock, Jeffery L.; McNeish, John] Pfizer Global Res & Dev, Genet Technol, Groton, CT 06340 USA. [Hong, Eun-Gyoung, Jun, John Y.; Ko, Hwi Jin, Kim, Jason K.] Penn State Coll Med, Penn State Mouse Metab Phenotyping Ctr, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Swift, Amy L.; Winer, Mike, Chen, Denise, Wu, Min] Seahorse Biosci, N Billerica, MA 01862 USA. [Leon, Lisa R.] USA, Thermal Mt Med Div, Environm Med Res Inst, Natick, MA 01760 USA. [Shaw, Andrey S.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. [Shaw, Andrey S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.
    1. Year: 2009
  2. Journal: Cell Metabolism
    1. 10
    2. 5
    3. Pages: 366-378
  4. Type of Article: Article
  1. 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.

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  2. DOI: 10.1016/j.cmet.2009.09.010
  3. PMID: 19883615

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