Costanzo-Garvey, Diane L., Pfluger, Paul, Stock, Jeffery L., Schreiner, Aimee, Hong, Eun-Gyoung, Volle, Deanna J., Treece, Tina, Wu, Ming-Hoi, Shaw, Andrey S., Ko, Hwi Jin, Mcneish, John, Kim, Jason K., Tschã-p, Matthias H., and Lewis, Robert E.
Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) are molecular scaffolds that regulate the intensity and duration of signaling through the Raf/MEK/ERK kinase cascade. KSR1[sup -/-] mice were lean but glucose intolerant. Homozygous disruption of KSR2 caused marked obesity, elevated plasma leptin and insulin levels, and intolerance to exogenous glucose and insulin. In hyperinsulinemic (2.5 mU/kg/min)-euglycemic clamp studies, the rate of glucose infused to maintain euglycemia (∼6 mM) was reduced by 60% in KSR2[sup -/-] mice as compared to wild-type (vet) mice. Basal hepatic glucose production (HGP) was significantly decreased in KSR2[sup -/-] mice, and hepatic insulin action, as reflected by insulin-mediated percent suppression of basal HGP, was reduced by more than 30%. Insulin-stimulated whole body glucose turnover was markedly decreased in KSR2[sup -/-] mice, indicating that KSR2 deletion caused insulin resistance in liver and peripheral tissues. Whole body glycolysis and glycogen plus lipid synthesis were similarly reduced in KSR2[sup -/-] mice. These data am consistent with the markedly reduced glycogen content in the livers and glycolytic muscle of KSR2[sup -/-] mice. Insulin-stimulated glucose uptake in skeletal muscle and adipose tissues was reduced b), 50-80% in KSR2[sup -/-] mice. Surprisingly, KSR2[sup -/-] mice are hypophagic, more physically active and exhibit a decreased respiratory quotient in comparison to wt mice. However, total energy expenditure of KSR2[sup -/-] mice is significantly lower compared to wt mice. We conclude that compensatory processes controlled by the central nervous system are still intact, hut not sufficient to restore a severely decreased resting thermogenesis. These data indicate that KSR proteins affect insulin sensitivity and glucose metabolism in peripheral tissue. Coupled with the potent effect of KSR proteins in regulating Raf and MEK activation, these observations suggest a previously unidentified, but physiologically important, role for these molecular scaffolds in regulating cellular metabolism. [ABSTRACT FROM AUTHOR]