Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1
Copyright policy )Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1
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-specificSirt1knock-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.SIGNIFICANCE STATEMENTPrevious 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, includingSirt1, 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.
- University of Alabama at Birmingham United States
Male, Neurons, Memory Disorders, Excitatory Postsynaptic Potentials, Mice, Transgenic, Recognition, Psychology, DNA Methylation, Diet, High-Fat, Hippocampus, Antioxidants, Mice, Inbred C57BL, Disease Models, Animal, Mice, Prosencephalon, Gene Expression Regulation, Dietary Supplements, Exploratory Behavior, Animals, Insulin, Obesity
Male, Neurons, Memory Disorders, Excitatory Postsynaptic Potentials, Mice, Transgenic, Recognition, Psychology, DNA Methylation, Diet, High-Fat, Hippocampus, Antioxidants, Mice, Inbred C57BL, Disease Models, Animal, Mice, Prosencephalon, Gene Expression Regulation, Dietary Supplements, Exploratory Behavior, Animals, Insulin, Obesity
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