Title | KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Pearce, LR, Atanassova, N, Banton, MC, Bottomley, B, van der Klaauw, AA, Revelli, J-P, Hendricks, A, Keogh, JM, Henning, E, Doree, D, Jeter-Jones, S, Garg, S, Bochukova, EG, Bounds, R, Ashford, S, Gayton, E, Hindmarsh, PC, Shield, JPH, Crowne, E, Barford, D, Wareham, NJ, O'Rahilly, S, Murphy, MP, Powell, DR, Barroso, I, I Farooqi, S |
Corporate Authors | |
Journal | Cell |
Volume | 155 |
Issue | 4 |
Pagination | 765-77 |
Date Published | 2013 Nov 07 |
ISSN | 1097-4172 |
Keywords | Age Factors, Age of Onset, Amino Acid Sequence, Animals, Child, Energy Metabolism, Fatty Acids, Female, Glucose, Humans, Hyperphagia, Insulin Resistance, Male, MAP Kinase Signaling System, Mice, Models, Molecular, Molecular Sequence Data, Obesity, Oxidation-Reduction, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins B-raf, Sequence Alignment |
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. |
DOI | 10.1016/j.cell.2013.09.058 |
Alternate Journal | Cell |
Citation Key | 10.1016/j.cell.2013.09.058 |
PubMed ID | 24209692 |
PubMed Central ID | PMC3898740 |
Grant List | MC_UU_12015/1 / / Medical Research Council / United Kingdom MC_UP_1201/6 / / Medical Research Council / United Kingdom G0900554 / / Medical Research Council / United Kingdom G0600717 / / Medical Research Council / United Kingdom G0502115 / / Medical Research Council / United Kingdom 098497 / / Wellcome Trust / United Kingdom 100574 / / Wellcome Trust / United Kingdom WT091310 / / Wellcome Trust / United Kingdom MC_U106179471 / / Medical Research Council / United Kingdom 098497/Z/12/Z / / Wellcome Trust / United Kingdom 077016/Z/05/Z / / Wellcome Trust / United Kingdom 096106/Z/11/Z / / Wellcome Trust / United Kingdom |