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KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.

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.

Pubmed ID: 19883615

Authors

  • Costanzo-Garvey DL
  • Pfluger PT
  • Dougherty MK
  • Stock JL
  • Boehm M
  • Chaika O
  • Fernandez MR
  • Fisher K
  • Kortum RL
  • Hong EG
  • Jun JY
  • Ko HJ
  • Schreiner A
  • Volle DJ
  • Treece T
  • Swift AL
  • Winer M
  • Chen D
  • Wu M
  • Leon LR
  • Shaw AS
  • McNeish J
  • Kim JK
  • Morrison DK
  • Tschöp MH
  • Lewis RE

Journal

Cell metabolism

Publication Data

November 3, 2009

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK52809
  • Agency: NIDDK NIH HHS, Id: DK56863
  • Agency: NIDDK NIH HHS, Id: DK59630
  • Agency: NIDDK NIH HHS, Id: DK69987
  • Agency: NCRR NIH HHS, Id: P20 RR016469
  • Agency: NIDDK NIH HHS, Id: R01 DK052809
  • Agency: NIDDK NIH HHS, Id: R01 DK052809-12
  • Agency: NIDDK NIH HHS, Id: R01 DK080756
  • Agency: Intramural NIH HHS, Id: ZIA BC011107-02

Mesh Terms

  • AMP-Activated Protein Kinases
  • Adipose Tissue
  • Animals
  • COS Cells
  • Cells, Cultured
  • Cercopithecus aethiops
  • Energy Metabolism
  • Fatty Acids
  • Glucose
  • Glycolysis
  • Insulin Resistance
  • MAP Kinase Signaling System
  • Mice
  • Mice, Knockout
  • Obesity
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Thermogenesis