title: KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.
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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Costanzo-Garvey
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Michele K
authors.initials: MK
authors.lastname: Dougherty
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Stock
authors.forename: Matthew
authors.initials: M
authors.lastname: Boehm
authors.forename: Oleg
authors.initials: O
authors.lastname: Chaika
authors.forename: Mario R
authors.initials: MR
authors.lastname: Fernandez
authors.forename: Kurt
authors.initials: K
authors.lastname: Fisher
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kortum
authors.forename: Eun-Gyoung
authors.initials: EG
authors.lastname: Hong
authors.forename: John Y
authors.initials: JY
authors.lastname: Jun
authors.forename: Hwi Jin
authors.initials: HJ
authors.lastname: Ko
authors.forename: Aimee
authors.initials: A
authors.lastname: Schreiner
authors.forename: Deanna J
authors.initials: DJ
authors.lastname: Volle
authors.forename: Tina
authors.initials: T
authors.lastname: Treece
authors.forename: Amy L
authors.initials: AL
authors.lastname: Swift
authors.forename: Mike
authors.initials: M
authors.lastname: Winer
authors.forename: Denise
authors.initials: D
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Leon
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.forename: John
authors.initials: J
authors.lastname: McNeish
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
mesh_terms: 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
chemical_list: D005227:Fatty Acids; C542241:KSR2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose