Repository logo
 

KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.


Type

Article

Change log

Authors

Pearce, Laura R 
Atanassova, Neli 
Banton, Matthew C 
Bottomley, Bill 
van der Klaauw, Agatha A 

Abstract

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Description

Keywords

Age Factors, Age of Onset, Amino Acid Sequence, Animals, Child, Energy Metabolism, Fatty Acids, Female, Glucose, Humans, Hyperphagia, Insulin Resistance, MAP Kinase Signaling System, Male, Mice, Models, Molecular, Molecular Sequence Data, Obesity, Oxidation-Reduction, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Proto-Oncogene Proteins B-raf, Sequence Alignment

Journal Title

Cell

Conference Name

Journal ISSN

0092-8674
1097-4172

Volume Title

155

Publisher

Cell Press (Elsevier)
Sponsorship
Wellcome Trust (096106/Z/11/Z)
Wellcome Trust (098497/Z/12/Z)
Medical Research Council (G0502115)
Medical Research Council (G0900554)
Medical Research Council (MC_UU_12012/1)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (G0600717)
Medical Research Council (MC_UU_12012/5/B)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
Wellcome Trust (099038/Z/12/Z)
Wellcome Trust (100574/Z/12/Z)
Medical Research Council (MC_U106179471)
Wellcome Trust (091310/Z/10/Z)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)
This work was supported by the Wellcome Trust (098497/Z/12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (ISF and LRP), Medical Research Council (MC_U106179471) (NW), NIHR Cambridge Biomedical Research Centre (ISF, IB and SOR), and European Research Council (ISF). This study makes use of data generated by the UK10K Consortium (WT091310). A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org.