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.

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

“…The NCOA1 gene in adipocytes has also been shown to be associated with metabolic disease [87][88][89]. The KSR2 gene [60,90,91] and FGF21 [92][93][94] are also integrated genes in the network associated with obesity, Figure 7 and S3. Therefore, a number of the genes and pathways identified in Figure 7 and S3 provide potential therapeutic targets for adipocytes associated with obesity and metabolic disease.…”

Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome

“…Individuals carrying the KSR2 loss-of-function mutations exhibited childhood hyperphagia, reduced basal metabolic rate, and severe insulin resistance [44]. Recapitulating these metabolic phenotypes observed in humans, mice that are deficient in Ksr2 develop profound obesity [43, 45], glucose intolerance, and insulin resistance in liver, muscle and adipose tissues [46, 47], possibly due to reduced AMPK activation leading to impairment of fatty acid oxidation and enhancement of triglyceride storage [43]. Identification of a novel variant associated with MetS in our study showed that, in addition to the previously identified rare KSR2 mutations [44], common variants in KSR2 contribute to metabolic disorders.…”

Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis

“…Insulin resistance appears to be secondary to the obesity, as dietary restriction after weaning prevents obesity and glucose intolerance in KSR2 −/− mice. Insulin resistance returns when KSR2 −/− mice are fed ad libitum [13] .…”