Costanzo-Garvey, Diane L; Pfluger, Paul T; Dougherty, Michele K; Stock, Jeffery L; Boehm, Matthew; Chaika, Oleg; Fernandez, Ma R; Fisher, Kurt; Kortum, Robert L; Hong, Eun- G; Jun, John Y; Ko, Hwi J; 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, Matt H; Lewis, Rob E
description
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.
