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

Cell metabolism | Nov 3, 2009

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 RIS Download

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

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK52809
  • Agency: NIDDK NIH HHS, Id: DK59630
  • Agency: NIDDK NIH HHS, Id: R01 DK069987
  • Agency: NIDDK NIH HHS, Id: P01 DK056863
  • Agency: NCRR NIH HHS, Id: P20 RR016469
  • Agency: NCI NIH HHS, Id: P30 CA036727
  • Agency: NIDDK NIH HHS, Id: R01 DK052809
  • Agency: NIDDK NIH HHS, Id: DK56863
  • Agency: NIDDK NIH HHS, Id: U24 DK059630
  • Agency: Intramural NIH HHS, Id: ZIA BC011107-02
  • Agency: NIDDK NIH HHS, Id: R01 DK080756
  • Agency: NIDDK NIH HHS, Id: R01 DK052809-12
  • Agency: NIDDK NIH HHS, Id: DK69987

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