Author/Authors :
Laura R. Pearce، نويسنده , , Neli Atanassova، نويسنده , , Matthew C. Banton، نويسنده , , Bill Bottomley، نويسنده , , Agatha A. van der Klaauw، نويسنده , , Jean-Pierre Revelli، نويسنده , , Audrey Hendricks، نويسنده , , Julia M. Keogh، نويسنده , , Elana Henning، نويسنده , , Deon Doree، نويسنده , , Sabrina Jeter-Jones، نويسنده , , Sumedha Garg، نويسنده , , Elena G. Bochukova، نويسنده , , Rebecca Bounds، نويسنده , , Sofie Ashford، نويسنده , , Emma Gayton، نويسنده , , Peter C. Hindmarsh، نويسنده , , Julian P.H. Shield، نويسنده , , Elizabeth Crowne، نويسنده , , David Barford and Benjamin G Neel، نويسنده , , et al.، نويسنده ,
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-MEK-ERK 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.