Pearce, LR;
Atanassova, N;
Banton, MC;
Bottomley, B;
van der Klaauw, AA;
Revelli, JP;
Hendricks, A;
... Farooqi, IS; + view all
(2013)
KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.
Cell
, 155
(4)
pp. 765-777.
10.1016/j.cell.2013.09.058.
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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.
| Type: | Article |
|---|---|
| Title: | KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cell.2013.09.058 |
| Publisher version: | http://dx.doi.org/10.1016/j.cell.2013.09.058 |
| Language: | English |
| Additional information: | © 2013 The Authors. Published by Elsevier Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| 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 Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins B-raf, Sequence Alignment |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1423631 |
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