UAB researchers find that epigenetic changes
associated with chronic obesity alter expression of memory-related genes in the
brain.
Newswise,
January 27, 2016 – University
of Alabama at Birmingham researchers are probing how obesity makes
memory goes bad, and the underlying molecular mechanism that drives this
decline.
They
have found that epigenetic changes dysregulate memory-associated genes, and a
particular enzyme in brain neurons of the hippocampus appears to be a link
between chronic obesity and cognitive decline. Their work is published in the
Jan. 27 issue of Journal of Neuroscience.
Obesity
plagues developed nations, and among the numerous negative health outcomes
associated with obesity is a memory impairment that is seen in middle-aged and
older obese people.
The
cause of this decline? Experiments with obese rodents have given a clue:
altered gene expression in the hippocampus area of the brain. Until now, the
reasons gene expression was changed, as well as the mechanism by which obesity
leads to pathogenic memory impairment, have not been known.
There
was one suspect: epigenetic dysregulation in neurons of the hippocampus.
Foundational experiments over the past decade have linked the creation of
long-term memories to changes in DNA methylation and hydroxymethylation —
changes caused by epigenetic mechanisms that sit above the level of the genes.
Such
lasting molecular changes to DNA appear to play an important role in promoting
or suppressing memory formation through their ability to increase or reduce the
expression of genes that help brain neurons create new synaptic connections.
UAB
researchers have now shown that epigenetic changes are indeed associated with
changes in the expression of memory-associated genes within the hippocampus of
obese mice, and these epigenetic changes correlate with diminished object
location spatial memory in the obese mice.
The
UAB researchers have also implicated reduced amounts of one particular
memory-associated gene product — SIRT1 — as the principal pathogenic cause of
obesity-induced memory impairment. The hippocampus subregion of the brain is
important for consolidation of long-term memory.
Corresponding
author J. David Sweatt, Ph.D., first author Frankie D. Heyward, Ph.D., and
colleagues in the UAB Department of Neurobiology, Evelyn F. McKnight Brain Institute, write that these data
“provide the first evidence that high-fat-diet-induced obesity leads to the
time-dependent development of aberrant epigenetic modifications within the
hippocampus, as well as corresponding reduction in the expression of various
memory-related genes.”
Sweatt
noted, “We feel this is a very exciting finding that identifies a new linkage
between diet, epigenetics and cognitive function, especially in light of the
burgeoning obesity epidemic in the U.S. and elsewhere.”
This
work, they write, “offers a novel working model that may serve as a conceptual
basis for the development of therapeutic interventions for obesity-induced
memory impairment.”
In
details about the cause of altered gene expression, the UAB researchers found
that:
• Mice with diet-induced obesity at 20 weeks had impaired performance in object
location memory tests, and their hippocampus had impaired synaptic plasticity,
as measured by long-term potentiation.
• Four memory-associated genes — Ppargc1a, Ppp1cb, Reln and Sirt1 —
showed significantly decreased gene expression at 23 weeks of diet-induced
obesity, as has been seen before, and the latter three had significantly
increased DNA methylation in their gene promoter regions. Increased methylation
is known to decrease gene expression. Furthermore, the Sirt1 promoter
region also had significantly decreased DNA hydroxymethylation. Gene expression
increases or decreases as DNA hydroxymethylation increases or decreases.
• Obesity-induced memory impairment develops over time. At just 13 weeks of
diet-induced obesity, seven weeks earlier than the experiments above, mice did
not have significant object location memory impairment, and at 16 weeks of
diet-induced obesity, also seven weeks earlier than above, none of the genes
showed significant increases in DNA methylation. Only one gene at 16 weeks — Ppargc1a —
showed significant decreases in gene expression and DNA hydroxymethylation.
To
probe the mechanism by which obesity leads to pathogenic memory impairment, the
UAB researchers focused on the gene Sirt1, which makes an enzyme that is active
in the neuron during energy expenditure and fat mobilization.
This
enzyme appears to be depleted and dysfunctional in obesity, and the deletion of
the Sirt1 gene in the brain shortly after birth is known to impair
memory and the ability to form new neural synapses. These roles for the SIRT1
gene product — in both high-fat-diet-induced molecular pathology and in memory
impairment — suggest that it might be a link between chronic obesity and
cognitive decline.
Heyward,
Sweatt and colleagues found that the hippocampus of obese mice had
significantly diminished protein expression of SIRT1, and a substrate of the
enzyme, acetlylated-p53, was significantly increased, suggesting reduced
enzymatic activity. Also, a targeted deletion of Sirt1 in the
forebrain region that includes the hippocampus at age 8-12 weeks showed
decreased Sirt1 mRNA and protein in the hippocampus, and these mice
showed impaired object-location memory when tested two weeks later.
Furthermore,
chemical activation of SIRT1 in diet-induced obese mice by feeding them
resveratrol showed decreased levels of acetylated-p53, suggesting increased
SIRT1 enzymatic activity, and the resveratrol-fed obese mice had a normal
object-location memory, as compared with the control obese mice.
The
resveratrol-fed obese mice did not show an enhanced memory compared with normal
mice. This suggests that resveratrol preserved their hippocampus-dependent
spatial memory and SIRT1 function in the hippocampus.
Besides
Heyward and Sweatt, co-authors of the paper, “Obesity weighs down memory
through a mechanism involving the neuroepigenetic dysregulation of Sirt1,” are
Daniel Gilliam, Mark Coleman, Cristin Gavin, Ph.D., Jing Wang, Ph.D., Garrett
Kaas, Ph.D., Richard Trieu, John Lewis and Jerome Moulden, all of the UAB
Department of Neurobiology.
Heyward
is now a postdoctoral fellow at Harvard Medical School, the Broad Institute and
Beth Israel Deaconess Medical Center. While at UAB, Heyward was supported by a
UNCF/Merck Graduate Science Research Dissertation Fellowship that helps train
and develop African-American biomedical scientists.
About
10 years ago, Sweatt’s lab made the seminal discovery that everyday experiences
tap into epigenetic mechanisms in subregions of the brain, and the resulting
epigenetic changes in DNA are critically important for long-term memory
formation and the stable storage of long-term memory. The 2007 Neuron paper
“Covalent modification of DNA regulates memory formation,” by Courtney Miller,
Ph.D., and Sweatt, was the first to show
that
active regulation of the chemical structure of DNA is involved in learning and
experience-driven changes in the brain.
Obesity and cognitive decline
Evidence that suggests a link between the two includes:
• People ages 40-45 who were obese had a 74 percent increased risk of dementia
21 years later, and those who were overweight had a 35 percent greater risk.
This study cohort had 10,276 men and women. Whitmer, RA, et al., BMJ 2005.
• A study of 2,223 healthy workers found that a higher body-mass index was
associated with lower cognitive scores, after adjustment for age, sex,
educational level, blood pressure, diabetes and other co-variables. Also, a
higher BMI at baseline was associated with higher cognitive decline at a
follow-up five years later. Cournot, M., et al., Neurology 2006.
• Metabolic syndrome in 73 people with an average age of 60 was associated with
significant reductions in recall and overall intellectual functioning, compared
with age- and education-matched controls. Hassenstab, J.J., et al., Dementia
and Geriatric Cognitive Disorders 2010.
• A study of 8,534 twin individuals who were 65 or older showed that being
overweight or obese at mid-life, with an average age of 43, was related to
later dementia at the older age. Xu, W.L., et al., Neurology 2011.
About UAB
Known for its innovative and interdisciplinary approach to education at both
the graduate and undergraduate levels, the University of Alabama at Birmingham
is an internationally renowned research university and academic medical center
and the state of Alabama’s largest employer, with some 23,000 employees and an
economic impact exceeding $5 billion annually on the state. The five pillars of
UAB’s mission include education, research, patient care, community service and
economic development. UAB: Knowledge
that will change your world. Learn more at www.uab.edu