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.

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

“…46 Results demonstrated an increase in Hdac2 gene expression in old animals compared with younger ones, and notably, RV was able to reduce this deacetylase expression in both groups of old mice. In addition to cytosolic deacetylase activity, as we previously pointed out, SIRT1 is also an enzyme participating in histone deacetylation and then in the epigenetic control of gene expression, 47 and RV was able to increase Sirt1 expression in RV-fed old mice.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Activation of inflammatory microglia may contribute to the loss of synapses on hippocampal dentate granule neuron dendrites caused by obesity and diabetes (Stranahan et al, 2008b; Hao et al, 2016). The ability of neurons to respond adaptively to bioenergetic and oxidative stress is compromised by excessive energy intake as indicated by reduced expression of BDNF (Stranahan et al, 2008b), PGC-1α (Morselli et al, 2014), and SIRT1 (Heyward et al, 2016). Obese and diabetic rodents exhibit elevated glucocorticoid levels, which can suppress BDNF expression and impair hippocampal synaptic plasticity and neurogenesis (Stranahan et al, 2008a; Wosiski-Kuhn et al, 2014).…”

Molecular Imaging of Sirtuin1 Expression–Activity in Rat Brain Using Positron-Emission Tomography–Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide

“…45 Changes in SIRT1 expression may be quite dynamic in many of these pathological conditions, such as in the progressive decline in cognitive-memory performance with increasing body-mass index in animals with dietary-induced obesity; however, treatment with a SIRT1-targeted activator, resveratrol, ameliorates much of the hippocampal neuro-degeneration. 46 Alternatively, increased SIRT1-expression levels have been noted in other neurodegenerative diseases, such as Huntington’s disease, which has led to exploratory clinical trials with SIRT1 selective inhibitors, such as Selisistat (EX-527) 47 . 15e Because of the pleiotropic role of SIRT1 in neurodegeneration, there is an ongoing debate in the literature regarding the effectiveness of SIRT1 activators versus inhibitors for the treatment of neurodegeneration.…”