title: Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1.
abstract: Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specific Sirt1 knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus.
  
  
  CONCLUSIONS
  Previous studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the development of therapeutic interventions for obesity-induced memory impairment.
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Frankie D
authors.initials: FD
authors.lastname: Heyward
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gilliam
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Coleman
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Cristin F
authors.initials: CF
authors.lastname: Gavin
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Garrett
authors.initials: G
authors.lastname: Kaas
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Richard
authors.identifier: http://orcid.org/0000-0002-4796-2202
authors.initials: R
authors.lastname: Trieu
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: John
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Jerome
authors.initials: J
authors.lastname: Moulden
authors.affiliation: Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294 dsweatt@uab.edu.
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000178:diet therapy / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology*; D016548:Prosencephalon / Q000473:pathology; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects / Q000528:radiation effects; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000975:Antioxidants; D007328:Insulin; D013267:Stilbenes; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: DNA methylation; Sirt1; epigenetics; high-fat diet; memory; obesity
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