A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction

摘要: Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD+-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects calorie on neuronal plasticity, memory social behavior abolished in mice lacking cAMP responsive-element binding (CREB)-1 forebrain. Moreover, CREB deficiency drastically reduces expression Sirt-1 induction genes relevant to metabolism survival cortex hippocampus dietary-restricted animals. Biochemical studies reveal a complex interplay between Sirt-1: directly regulates transcription sirtuin cells by chromatin; Sirt-1, turn, is recruited DNA promotes CREB-dependent target gene peroxisome proliferator-activated receptor-γ coactivator-1α NO Synthase. Accordingly, targets markedly reduced Sirt KO are, like CREB-deficient mice, poorly responsive restriction. Thus, above circuitry, modulated nutrient availability, links energy with neurotrophin signaling, participates adaptation restriction, potentially accelerated aging overnutrition diabetes.