Obesity‐dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2−/− mice

Disruption of KSR2 in humans and mice decreases metabolic rate and induces obesity, coincident with dysregulation of glucose homeostasis. Relative to wild‐type mice, ksr2−/− mice are small prior to weaning with normal glucose tolerance at 6 weeks of age, but demonstrate excess adiposity by 9 weeks and glucose intolerance by 12–14 weeks. Defects in AICAR tolerance, a measure of whole‐body AMPK activation, are detectable only when ksr2−/− mice are obese. Food restriction prevents the obesity of adult ksr2−/− mice and normalizes glucose and AICAR sensitivity. Obesity and glucose intolerance return when ad lib feeding is restored to the diet‐restricted mice, indicating that glucose dysregulation is secondary to obesity in ksr2−/− mice. The phenotype of C57BL/6 ksr2−/− mice, including obesity and obesity‐related dysregulation of glucose homeostasis, recapitulates that of humans with KSR2 mutations, demonstrating the applicability of the C57BL/6 ksr2−/− mouse model to the study of the pathogenesis of human disease. These data implicate KSR2 as a physiological regulator of glucose metabolism during development affecting energy sensing, insulin signaling, and lipid storage, and demonstrate the value of the C57BL/6 ksr2−/− mouse model as a unique and relevant model system in which to develop and test therapeutic targets for the prevention and treatment of obesity, type 2 diabetes, and obesity‐related metabolic disorders. A fraction of individuals with obesity‐induced insulin resistance and diabetes respond to diet with improved glucose metabolism. The phenotype of C57BL/6 ksr2−/− mice, including obesity and obesity‐related dysregulation of glucose homeostasis, recapitulates that of humans with KSR2 mutations. These data show that the glucose intolerance and AICAR insensitivity that accompanies KSR2 disruption in mice is preventable or reversible by diet, suggesting that dietary intervention in humans with KSR2 mutations should have similar effects.