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

Malinda D. Henry, Diane L. Costanzo-Garvey, Paula J. Klutho, Robert E Lewis

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Article numbere12053
JournalPhysiological Reports
Volume2
Issue number7
DOIs
Publication statusPublished - Jan 1 2014

    Fingerprint

Keywords

  • AMPK
  • Glucose metabolism
  • Insulin resistance
  • KSR2
  • Obesity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this