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

Salvatore Fusco, Cristian Ripoli, Maria Vittoria Podda, Sofia Chiatamone Ranieri, Lucia Leone, Gabriele Toietta, Michael W. McBurney, Günther Schütz, Antonella Riccio, Claudio Grassi, Tommaso Galeotti, Giovambattista Pani

Research output: Contribution to journalArticle

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 dietaryrestricted 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 neuronalNOSynthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of SirtKO 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.

Original languageEnglish
Pages (from-to)621-626
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number2
DOIs
Publication statusPublished - Jan 10 2012

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