title: Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2-/- mice.
abstract: 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.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: MaLinda D
authors.initials: MD
authors.lastname: Henry
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Costanzo-Garvey
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Klutho
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
keywords: AMPK; KSR2; glucose metabolism; insulin resistance; obesity