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.
Costanzo-Garvey
Diane L
DL
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA.
Pfluger
Paul T
PT
Dougherty
Michele K
MK
Stock
Jeffery L
JL
Boehm
Matthew
M
Chaika
Oleg
O
Fernandez
Mario R
MR
Fisher
Kurt
K
Kortum
Robert L
RL
Hong
Eun-Gyoung
EG
Jun
John Y
JY
Ko
Hwi Jin
HJ
Schreiner
Aimee
A
Volle
Deanna J
DJ
Treece
Tina
T
Swift
Amy L
AL
Winer
Mike
M
Chen
Denise
D
Wu
Min
M
Leon
Lisa R
LR
Shaw
Andrey S
AS
McNeish
John
J
Kim
Jason K
JK
Morrison
Deborah K
DK
Tschöp
Matthias H
MH
Lewis
Robert E
RE
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004734:Energy Metabolism / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis / Q000502:physiology
D005227:Fatty Acids; C542241:KSR2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose