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

TitleKSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.
Publication TypeJournal Article
Year of Publication2013
AuthorsPearce, 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
JournalCell
Volume155
Issue4
Pagination765-77
Date Published2013 Nov 07
ISSN1097-4172
KeywordsAge 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.

DOI10.1016/j.cell.2013.09.058
Alternate JournalCell
Citation Key10.1016/j.cell.2013.09.058
PubMed ID24209692
PubMed Central IDPMC3898740
Grant ListMC_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