title: A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction.
abstract: 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 of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes.
authors.affiliation: Laboratory of Cell Signaling, Institute of General Pathology, Universita' Cattolica School of Medicine, 00168 Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fusco
authors.forename: Cristian
authors.initials: C
authors.lastname: Ripoli
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Podda
authors.forename: Sofia Chiatamone
authors.initials: SC
authors.lastname: Ranieri
authors.forename: Lucia
authors.initials: L
authors.lastname: Leone
authors.forename: Gabriele
authors.initials: G
authors.lastname: Toietta
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Antonella
authors.initials: A
authors.lastname: Riccio
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
authors.forename: Tommaso
authors.initials: T
authors.lastname: Galeotti
authors.forename: Giovambattista
authors.initials: G
authors.lastname: Pani
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D031204:Caloric Restriction; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism*; D011597:Psychomotor Performance; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D012919:Social Behavior
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1