KSR2 Is an Essential Regulator of AMP Kinase, Energy Expenditure, and Insulin Sensitivity

被引：110

作者：

Costanzo-Garvey, Diane L. ^{[1
]}

Pfluger, Paul T. ^{[2
]}

Dougherty, Michele K. ^{[3
]}

Stock, Jeffery L. ^{[4
]}

Boehm, Matthew ^{[1
]}

Chaika, Oleg ^{[1
]}

Fernandez, Mario R. ^{[1
]}

Fisher, Kurt ^{[1
]}

Kortum, Robert L. ^{[1
]}

Hong, Eun-Gyoung ^{[5
]}

Jun, John Y. ^{[5
]}

Ko, Hwi Jin ^{[5
]}

Schreiner, Aimee ^{[1
]}

Volle, Deanna J. ^{[1
]}

Treece, Tina ^{[1
]}

Swift, Amy L. ^{[6
]}

Winer, Mike ^{[6
]}

Chen, Denise ^{[6
]}

Wu, Min ^{[6
]}

Leon, Lisa R. ^{[7
]}

Shaw, Andrey S. ^{[8
,9
]}

McNeish, John ^{[4
]}

Kim, Jason K. ^{[5
]}

Morrison, Deborah K. ^{[3
]}

Tschoep, Matthias H. ^{[2
]}

Lewis, Robert E. ^{[1
]}

机构：

[1] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA

[2] Univ Cincinnati, Dept Med, Obes Res Ctr, Cincinnati, OH 45237 USA

[3] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA

[4] Pfizer Global Res & Dev, Genet Technol, Groton, CT 06340 USA

[5] Penn State Coll Med, Penn State Mouse Metab Phenotyping Ctr, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA

[6] Seahorse Biosci, N Billerica, MA 01862 USA

[7] USA, Thermal Mt Med Div, Environm Med Res Inst, Natick, MA 01760 USA

[8] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA

[9] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

来源：

CELL METABOLISM | 2009年 / 10卷 / 05期

基金：

美国国家卫生研究院;

关键词：

ACTIVATED PROTEIN-KINASE; GLUCOSE-TRANSPORT; CELLULAR-ENERGY; SKELETAL-MUSCLE; IN-VIVO; SCAFFOLD; PHOSPHORYLATION; OBESITY; IDENTIFICATION; SUPPRESSOR;

D O I：

10.1016/j.cmet.2009.09.010

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：366 / 378

页数：13

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