@article{cf3123279ac1433e9916d2ec72726d5a,
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.",
keywords = "HUMDISEASE",
author = "Costanzo-Garvey, {Diane L.} and Pfluger, {Paul T.} and Dougherty, {Michele K.} and Stock, {Jeffery L.} and Matthew Boehm and Oleg Chaika and Fernandez, {Mario R.} and Kurt Fisher and Kortum, {Robert L.} and Hong, {Eun Gyoung} and Jun, {John Y.} and Ko, {Hwi Jin} and Aimee Schreiner and Volle, {Deanna J.} and Tina Treece and Swift, {Amy L.} and Mike Winer and Denise Chen and Min Wu and Leon, {Lisa R.} and Shaw, {Andrey S.} and John McNeish and Kim, {Jason K.} and Morrison, {Deborah K.} and Tsch{\"o}p, {Matthias H.} and Lewis, {Robert E.}",
note = "Funding Information: We thank the members of the Lewis laboratory for comments and criticism. M. Birnbaum (University of Pennsylvania) is thanked for his gift of the constitutively active AMPK construct. This work was supported by National Institutes of Health (NIH) grants to R.E.L. (DK52809) and M.H.T. (DK69987, DK59630, and DK56863) and by support from the Nebraska Research Initiative (to R.E.L.). M.R.F was supported by the Skala Fellowship, and M.B. was supported by the Bukey Fellowship from the University of Nebraska Medical Center (UNMC). K.F. was supported by a Physician/Scientist Training Award from the American Diabetes Association. The UNMC Microarray Core Facility receives partial support from NIH grant P20 RR016469. For those studies conducted at United States Army Research Institute Environmental Medicine (USARIEM), the opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or reflecting the views of the Army or the Department of Defense. Any citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement of approval of the products or services of these organizations. ",
year = "2009",
month = nov,
day = "4",
doi = "10.1016/j.cmet.2009.09.010",
language = "English (US)",
volume = "10",
pages = "366--378",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}