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: MaLinda D Henry, Diane L Costanzo-Garvey, Paula J Klutho, Robert E Lewis
• Journal: Physiological reports (Physiol Rep) Vol. 2 Issue 7 (Jul 01 2014) ISSN: 2051-817X [Print] United States
• PMID: 24997067 (Publication Type: Journal Article)
• Copyright: © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.