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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.

SUBMITTER: Costanzo-Garvey DL

PROVIDER: S-EPMC2773684 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.

Costanzo-Garvey Diane L DL 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 Kim Jason K JK Morrison Deborah K DK Tschöp Matthias H MH Lewis Robert E RE

Cell metabolism 20091101 5

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. ...[more]

PMID: 19883615

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Project description:The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform.To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5 (-/-) ).Ablation of ACSL5 reduced ACSL activity by ?80% in jejunal mucosa, ?50% in liver, and ?37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5 (-/-) , as compared to control ACSL5 (loxP/loxP) , mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5 (-/-) had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5 (-/-) mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (?16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (?13-fold) were increased in ACSL5 (-/-) as compared to ACSL5 (loxP/loxP) . Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1?) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5 (-/-) mice as compared to control mice.In summary, ACSL5 (-/-) mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.

Dataset Information

KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.

Publications

KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.

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