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

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.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.This is the final published version. It first appeared at http://www.cell.com/abstract/S0092-8674%2813%2901276-2

Guitar Ensemble February 19, 2016

Concert ProgramGuitar Ensemble February 19, 201

Guitar Ensemble February 6, 2015

Concert ProgramGuitar Ensemble February 6, 201

Evening of Excellence: Celebrating our Brechemin Scholarship Winners April 2, 2015

Concert ProgramEvening of Excellence: Celebrating our Brechemin Scholarship Winners April 2, 201

Michael Gibbs & Bill Frisell with the UW Symphony and Jazz Studies Faculty January 14, 2016

Concert ProgramMichael Gibbs & Bill Frisell with the UW Symphony and Jazz Studies Faculty January 14, 201

2015 Concerto Competition: Winds/Brass/Percussion November 23, 2015

Concert Program2015 Concerto Competition: Winds/Brass/Percussion November 23, 201

Baroque Ensemble February 24, 2015

Concert ProgramConcert program for the Baroque Ensemble February 24, 201