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

Salvatore Fusco, Cristian Ripoli, Lucia Leone, Claudio Grassi, Giovambattista Pani, Antonella Riccio, Tommaso Galeotti, Gabriele Toietta, Michael W. Mcburney, Günther Schütz

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

107 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)621-626
Numero di pagine6
RivistaProceedings of the National Academy of Sciences of the United States of America
Volume109
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • Analysis of Variance
  • Animals
  • Caloric Restriction
  • Cyclic AMP Response Element-Binding Protein
  • Gene Expression Regulation
  • Long-Term Potentiation
  • Male
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neuronal Plasticity
  • Neurons
  • Prosencephalon
  • Psychomotor Performance
  • Sirtuin 1
  • Social Behavior

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