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PMID: 19883615 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell metabolism ·Vol. 10 ·No. 5 ·2009-11-00 ·Pages 366-78

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

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.

MeSH Terms
AMP-Activated Protein Kinases/metabolism Adipose Tissue/metabolism Animals COS Cells Cells, Cultured Chlorocebus aethiops Energy Metabolism/physiology Fatty Acids/metabolism Glucose/metabolism Glycolysis/physiology Insulin Resistance/physiology MAP Kinase Signaling System/physiology Mice Mice, Knockout Obesity/etiology,metabolism Oxidation-Reduction Oxidative Phosphorylation Protein Serine-Threonine Kinases/antagonists & inhibitors,genetics,metabolism Thermogenesis/physiology
Chemicals
Fatty Acids KSR2 protein, mouse Protein Serine-Threonine Kinases AMP-Activated Protein Kinases Glucose
Authors & Affiliations
26 authors, click to expand affiliations / ORCID
Costanzo-Garvey Diane L
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA.
Pfluger Paul T
Dougherty Michele K
Stock Jeffery L
Boehm Matthew
Chaika Oleg
Fernandez Mario R
Fisher Kurt
Kortum Robert L
Hong Eun-Gyoung
Jun John Y
Ko Hwi Jin
Schreiner Aimee
Volle Deanna J
Treece Tina
Swift Amy L
Winer Mike
Chen Denise
Wu Min
Leon Lisa R
Shaw Andrey S
McNeish John
Kim Jason K
Morrison Deborah K
Tschöp Matthias H
Lewis Robert E
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Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1932-7420
DOI
10.1016/j.cmet.2009.09.010
Published
2009-11-00
Pages
366-78
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC2773684
Subset
IM
Grants
NIDDK NIH HHS · DK52809 · United States
NIDDK NIH HHS · R01 DK052809 · United States
NIDDK NIH HHS · DK56863 · United States
NIDDK NIH HHS · U24 DK059630 · United States
NIDDK NIH HHS · DK59630 · United States
NIDDK NIH HHS · R01 DK069987 · United States
NIDDK NIH HHS · P01 DK056863 · United States
NCRR NIH HHS · P20 RR016469 · United States
Intramural NIH HHS · ZIA BC011107-02 · United States
NIDDK NIH HHS · R01 DK080756 · United States
NIDDK NIH HHS · R01 DK052809-12 · United States
NIDDK NIH HHS · DK69987 · United States
Databases
GEO
GSE17923
External Links
PubMed source DOI: 10.1016/j.cmet.2009.09.010 PMC Full Text View journal details
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