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

Abstract

ObjectiveKinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance.MethodsMice bearing floxed alleles of KSR2 (KSR2fl/fl) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2fl/fl mice. Growth, body composition, food consumption, cold tolerance, insulin and free fatty acid levels, glucose, and AICAR tolerance were measured in gender and age matched KSR2−/− miceResultsNes-CreKSR2fl/fl mice lack detectable levels of KSR2 in the brain. The growth and onset of obesity of Nes-CreKSR2fl/fl mice parallel those observed in KSR2−/− mice. As in KSR2−/− mice, Nes-CreKSR2fl/fl are glucose intolerant with elevated fasting and cold intolerance. Male Nes-CreKSR2fl/fl mice are hyperphagic, but female Nes-CreKSR2fl/fl mice are not. Unlike KSR2−/− mice, Nes-CreKSR2fl/fl mice respond normally to leptin and AICAR, which may explain why the degree of obesity of adult Nes-CreKSR2fl/fl mice is not as severe as that observed in KSR2−/− animals.ConclusionsThese observations suggest that, in the brain, KSR2 regulates energy balance via control of feeding behavior and adaptive thermogenesis, while a second KSR2-dependent mechanism, functioning through one or more other tissues, modulates sensitivity to leptin and activators of the energy sensor AMPK.

Change in sexual signalling traits outruns morphological divergence across an ecological gradient in the post‐glacial radiation of the songbird genusJunco

“…GO terms associated with higher numbers of genes were related to membrane cellular components, catalytic and binding molecular functions as well as cellular and metabolic processes (Figure S3). Reported functions of the identified genes included the following: energy balance via glucose homeostasis, control of feeding behaviour and adaptive thermogenesis, as well as spermatogenesis (KSR2; Guo et al., 2017); neural morphogenesis (CNK2; Lim, Ritt, Zhou, & Morrison, 2014); angiogenesis and gonad development (Scrib; Michaelis et al., 2013) (see Table S3 for a complete list of genes and associated GO terms). The RDA based on the 23 SNPs linked to known functional genes recovered similar association signals along RDA1 compared to the analysis based on the entire SNP data set, with less pronounced orthogonality among explanatory variables.…”

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

“…Another possible mechanism for enhancing insulin resistance is through the increased phosphorylation status of β-3 adrenergic receptor in an ERK2-dependent manner, facilitating lipolysis [ 43 ]. Very interestingly, the elimination of kinase suppressor of Ras 2 (KSR2) in mice, a scaffold protein that coordinates Raf/MEK/ERK signaling pathway, causes insulin resistance and obesity [ 44 ]. Direct activation of PPAR-γ by ERK has been observed with a concomitant increase in insulin resistance, which could be suppressed by cyclin-dependent kinase 5 (CDK5) in a MEK-dependent manner [ 45 ].…”

Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras

“…Ksr2 variants in humans that impair Ras signaling or inhibit KSR2 interaction with AMPK also disrupt glucose metabolism and fatty acid oxidation 60 . Interestingly, KSR2 is almost exclusively expressed in the brain and pituitary 19 , 58 . Brain-specific disruption of KSR2 is sufficient to cause obesity and glucose intolerance in mice, though it does not perfectly recapitulate the phenotype of ksr2 –/– mice 19 .…”

“…Interestingly, KSR2 is almost exclusively expressed in the brain and pituitary 19 , 58 . Brain-specific disruption of KSR2 is sufficient to cause obesity and glucose intolerance in mice, though it does not perfectly recapitulate the phenotype of ksr2 –/– mice 19 . These observations show that KSR2 function in the brain plays a potent role in the regulation of energy balance.…”

“…CA2 is a proline-rich region without known function. A region in KSR2 between CA2 and CA3 is required for KSR interaction with AMPK, and mutations in this region inhibit this interaction 19 , 31 , 58 . CA3 is a cysteine-rich region containing an atypical C1 motif homologous to the cysteine-rich CR1 region in Raf that also contributes to KSR1 membrane localization 21 , 62 .…”