The brain plays a critical role in sensing energy demands and regulating fuel storage to maintain body weight within a tight range. Extensive analysis has identified key conserved genes and neural pathways that are critical in regulating energy balance.
Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that potently regulates energy consumption and expenditure. KSR2 coordinates the interaction of Raf/MEK/ERK signaling to facilitate signal transduction and regulate the intensity and duration of ERK signaling. KSR2 also promotes activation of the primary regulator of cellular energy homeostasis, 5’-adenosine monophosphate-activated protein kinase (AMPK).
Guo, Costanzo-Garvey, Smith et al. show that brain-specific disruption of KSR2 in mice is sufficient to reduce body temperature, promote cold intolerance, cause obesity, and impair glucose homeostasis, while elevating fasting insulin and free fatty acid levels in the blood. Disruption of KSR2 selectively in the brain causes hyperphagia in male, but not female, mice. Though still obese, adiposity in female mice lacking KSR2 in the brain is correspondingly reduced. These data demonstrate that KSR2 functions centrally to regulate energy balance through effects on feeding behavior and adaptive thermogenesis.Full Text