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Many recent publications in the field of epigenetic have focused on the role of epigenetic in learning and memory. Sir Francis Crick first proposed an epigenetic mechanism for memory in a letter to Nature in  and more than 30 years later, we are beginning to realize the truths in his hypothesis . The remainder of this section will focus on the interactions between environmental stimuli and how these events are recorded by changes to chromatin in the hippocampus, but for some nice reviews on the epigenetics of learning and memory, see those by Zovkic, Meagher, Lipsky, Day and Sweatt, and Woldemichael [5,].
A variety of environmental stimuli are able to induce epigenetic events in the hippocampus. Stressors such as social defeat or physical restraint activate the sympathetic nervous system and the hypothalamic-pituitary-adrenal HPA axisto produce behavioral alterations, such as enhancing social avoidance and an hedonia and changing eating patterns [40,41].
Rats exposed to a social defeat stress exhibited increased depressive-like behavior and had different hippocampal histone acetylation profiles when compared to their unstressed peers . Just 30 minutes following the social defeat stress, histone H3 became hyperacetylated in the hippocampus, an effect that increased during the 24 hours following the stress and then returned to baseline levels after 72 hours.
No effects of stress were seen in the amygdala or prefrontal cortex PFC in this study.
Psychosocial stress has been shown to differentially affect BDNF methylation in functional poles of the hippocampus, increasing methylation in the dorsal CA1 with a concurrent reduction in BDNF mRNA and decreasing methylation in the ventral CA3 , while restraint stress increased hydroxymethylation in the glucocorticoid receptor GR gene in the hippocampus . Enriching the living environments of rodents by the addition of tunnels, running wheels, or differently colored or textured toys to their home cages  or by exposure to these stimuli during defined sessions , can also affect the hippocampal epigenome, altering histone lysine methylation at BDNF promoters and increasing BDNF mRNA levels  and preventing aging-induced hydroxymethylation in genes important in axon guidance, learning, and memory .
Along similar lines, voluntary exercise induced several epigenetic changes in the hippocampi of rats. These data are presented in Section D. Much of the epigenetic machinery requires certain dietary nutrients for activity and there is clear evidence that diet and obesity have the ability to epigenetically reprogram many cell types [4,].
Specifically in the brain, most of the current literature on HFD intake and epigenetic focuses on the hypothalamus and on brain reward pathways, understandably, due to their long recognized role in consumptive behaviors. These changes are negatively correlated with transcription of these genes where tested.
This discrepancy could be the result of ineffective response of downstream targets. A study by Widiker and colleagues examined changes in methylation and expression of MCR4 in whole brain following HFD intake and found the gene to be significantly hypo ethylated, however they only detected a marginal increase in MCR4 expression . In these animals, increased caloric intake is likely ramping up an orexigenic pathways in an effort to maintain energy homeostasis, decreasing NPY and increasing POMC; however, despite these efforts, hyperphagia continues to eventually produce and maintain a state of obesity.
Funato et al  explored the idea that diet might epigenetically modify normal eating behavior via changes in HDAC histone deacety lase expression.
These data strongly suggest that a HFD influences epigenetic reprogramming in the hypothalamus. The obesity-related effects on gene expression are not described, but their data on the differences in the direction of HDAC expression changes suggests their role in relevant gene regulation is highly complex. This article goes on to show that for the ventromedial hypothalamus fasting reduces the number of cells that are positive for histone H3 lysine 14 acetylation H3K14Ac , a post-translational modification PTM associated with gene expression that supports memory formation.
Maternal or neonatal overfeeding increases the tendency toward adult obesity, diabetes, and CD, but how is this new metabolic program transmitted to off spring?
A critical view on transgenerational epigenetic inheritance in humans
There is initial support for the idea that overfeeding alters hypothalamic DNA methylation to reprogram gene expression  Overfed rats show hypothalamic hyper methylation and silencing of POMC promoter regions necessary for the control of POMC expression by leptin and insulin. As a result, in overfed rats, the POMC epiallele is not appropriately up regulated in the presence of increased leptin and insulin. In other words, these animals are epigenetically reprogrammed to be leptin and insulin resistant.
These data from the hypothalamus underscore the need to extend the study of food intake, as well as the search for answers to the problem of obesity, to brain regions with a different set of executive and behavioral controls. If we take into account the results from males, it appears that HFD dampens dopamine and opioid signaling.
Behavioral reports show consistency with this finding as HFD-exposed animals reduced preference for sucrose over water, a behavior consistent with reward hypo function [53,57,58]. This section and the previous make clear that environment and experience alter the hippocampal epigenome, and that diet and obesity alter epigenetic marks in the brain. The remainder of this review will address how these activities might interact.
In spite of the evidence that epigenetic controls hippocampal learning and memory formation and that hippocampal function is essential for normal eating behavior, the current literature only indirectly addresses how epigenetic controls in the hippocampus might oppose or support obesity. Several studies have examined epigenetic events following a contrary treatment: caloric restriction. Supporting this theory is evidence that 5hmC is positively correlated with transcription and chromatin accessibility and is enriched in gene bodies of highly expressed genes.
These findings agree with other evidence of the beneficial effects of caloric restriction on aging-associated diseases [64,65]. Though effects on specific epigenetic marks were not examined, caloric restriction has been shown to induce expression of sirtuin 1 SIRT1 , an NAD-dependent protein deacetylase involved in the epigenetic-based gene silencing.
In addition, there is evidence that diet and obesity rapidly alter the levels or activity of known epigenetic enzymes. HDAC4 is co localized with neurons containing orexin, serotonin, oxytocin, and vasopressin, to name a few; is known to play a role in synaptic plasticity; and has been investigated for its role in neurodegenerative disease . Though regulation of HDAC4 is thought to occur via shuttling this protein between the cytoplasm and the nucleus of the cell, the protein itself can be degraded by the activity of lip polysaccharide LPS or by apoptosis both of which are up regulated by HFD .
A large portion of the current epigenetic literature focuses on the second generation and early life effects of dietary manipulations.
"Do Diet and Obesity Reprogram the Hippocampus Via Epigenetic Mechanisms?"
There are a number of studies looking at the epigenetic consequences of variations in maternal care, stress, and drugs of abuse in the offspring. Their data suggest that HFD reduces the ability to carry out efficient repair, with obvious implications for other studies showing HFD is linked to cognitive deficiencies. Changes to the micronutrient profile of the maternal diet also affects in the hippocampi of offspring: a low choline maternal diet resulted in hypo me thylation of CpG islands near the promoter region of genes involved in angiogenesis , a methyl donor-deficient maternal diet was associated with changes in methylation status at a variety of CpG sites in the neuron tin gene , vitamin B 12 deficiency and omega-3 supplementation both resulted in global hyper methylation in the hippocampus , and a maternal diet high in fat soluble vitamins A, D, E, and K increased methylation in the gene for dopamine receptor 1 , all as measured in the offspring.
These studies demonstrate the ability of dietary nutrients to alter chromatin structure in the hippocampus. Aerobic exercise counters many of the negative health outcomes of obesity. A few studies relevant to our working hypothesis suggest that aerobic exercise enhances hippocampal neuronal plasticity and learning and memory performance in laboratory animals via epigenetic reprogramming. Treating rats with inhibitors of DNA methylation such as 5-azadeoxycytidine also results in increases in BDNF activity and improved performance in a forced swim test .
Hence, it appears that exercise improves hippocampal activity via epigenetic mechanism acting on an important neurotrophic factor, BDNF. When 3-month-old rats are given a single exercise session of 20 minutes on a motorized running wheel there is a 2-fold increase in hippocampal histone 4 lysine acetylation activities HAT and a 5-fold decrease histone deacetylase HDAC activity as assayed immediately or 1 hour after exercise .
The speed of this initial response suggests exercise stimulates extremely rapid changes in histone acetylation and its return to normal levels suggests that this acetylation turns over with a short half-life. Hippocampal nucleosomal histone 3 lysine 9 methylation H3K9Me levels are positively associated with neuronal gene silencing and reduced memory performance [80,81].
A single exercise session of 20 minutes or a chronic exercise protocol 2 weeks, 20 minutes daily produces a significant 2- to 4-fold reduction in hippocampal H3K9Me levels in young 3-month-old rats 1hour and 18 hours after exercise . The results were quite different for month-old rats, where exercise produced increases in H3K9Me. These results have not yet been directly connected to expected exercise-induced increases and decreases in neuronal gene expression in young and old rats, respectively.
- do diet and obesity reprogram the hippocampus via epigenetic mechanisms.
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- Obesity accelerates epigenetic aging of human liver.
Loss of memory and physical damage to the frontal cortex and hippocampus are among the first changes detected in the AD brain. Considering the data presented earlier, it is easy to imagine the connection between hippocampal damage and appetite disturbances. Controlled and quantified data from AD model mice lend the strongest support to the argument that AD contributes to eating and weight control disorders and that an early obese phenotype is due to epigenetic disorders of the hippocampus Figure 1.
However, APP is also a transcription factor that associates with the histone acetyl transferees Tip 60 to promote histone acetylation in the brain. If fed ad libitum various transgenic AD-model mice that over express the human amyloid precursor protein APP Swe tend toward early obesity, with or without other AD-inducing genetic defects .
In a study directly addressing obesity, the 3xTg mice carrying the APPswe mutation are obese by 2 months of age and this persists until 5 months, but by 12 months they are underweight .
do diet and obesity reprogram the hippocampus via epigenetic mechanisms
These mice are obese from 2 to 5 months e. Sixteen-month-old mice with the APPswe mutation are extremely defective in hippocampal-based spatial memory and learning potential as evidenced by their inability to efficiently learn to solve the Morris water maze. Remarkably, treating these mice with PBA restored their ability to solve the maze to the levels of wild type controls. There was a concomitant restoration of histone H3 and H4 acetylation levels in hippocampal neurons back up to the level so wild type.
The obvious implication here is that PBA restored hippocampal neuronal histone acetylation, neuronal gene expression, and neuron development to APPs we mice, thereby reestablishing more normal memory performance and that this phenotype was not related to plaque formation. The impact of PBA treatment on hippocampal controlled eating behavior, obesity, and metabolism in APPswe mice has not been reported. In summary, from these indirect data it is again reasonable to propose that epigenetic reprogramming of hippocampal neurons will alter the learning and memory processes with the potential to regulate temporal meal onset and food consumption, but the direct measurements of such relationships to obesity have not been made.
MRI data suggest that the hippocampus is involved in the emotional and visual responses to food that again are altered in obese or formerly obese individuals to support overeating. Preliminary interpretations of MRI data on the response of obese individuals to images or thoughts of food also suggest that hyperphagia and obesity parallel addictive behaviors like those for alcohol or other drugs of abuse, such as cocaine.
In support of this tantalizing view of obesity, the most effective weight loss programs, which overcome the weight-loss and regain paradigm for obese individuals, appear to involve not only diet and exercise, but long-term meetings and social activities with a continuous focus on behavioral modification, programs similar those treating alcohol and drug addiction .
This and other MRI-based studies point out the power of imaging the living brain to enhance obesity research. Independent physiological, live imaging, molecular genetics, epigenetic, cognitive disease, and behavioral studies suggest diet and obesity may damage hippocampal function and reduce normal restraint from hyperphagia, leading to obesity Figure 1. The epigenetic reprogramming of the hippocampus in relation to diet and obesity is not yet well tested.
By contrast, there is substantial evidence that the brain is in some way reprogrammed by diet and obesity, and that this reprogramming is likely to be epigenetic in nature.
Finally, there are data demonstrating that diet and obesity stimulate epigenetic changes in the hypothalamus and brain reward pathways that may alter behavior. The fusion of diverse arguments presented herein also makes clear that interdisciplinary information from experimental science is needed to understand the role of hippocampal functions in obesity.
Taking together these various research results, there is strong support for a cyclic relationship, where high fat diets and obesity cause dysfunction of the hippocampus, which in turn reinforces hyperphagia and continued obesity. The way forward: Accepting a strong role for the hippocampus in obesity, there is a real need for more comprehensive analyses of changes to its epigenetic controls as model animals respond to changes in diet, diet-induced changes in weight, and exercise. Comprehensive epigenetic studies of post-mortem human hippocampal samples comparing the molecular genetics and epigenetic changes among lean and obese individuals should help pinpoint epialleles or groups of interacting epialleles with relevance to obesity.
Only a few epitypes, primarily DNA methylation and three classes of PTMs, histone acetylation, methylations, and phosphorylation, have been studied in any detail in relation to epigenetic programming in the hippocampus . However there are several dozen other histone PTMs and a few additional modifications of cytosine, adenine, and thymidine counted among the known epigenetic marks.
It is likely that many of these changes in the epigenome are also involved in neuronal reprogramming in the response to stimuli such as diet, exercise, and obesity. Nucleosome position is determined in part by histone variant composition and in part by the nucleotide composition of certain base-pair repeats in the DNA sequence with the potential to make contact with each nucleosome [,]. Such DNA sequence polymorphisms are the likely cause of some multi generationally inherited epigenome-induced risks for obesity .
Neither nucleosome position nor histone variant composition has yet been reported in any detail for particular regions of the brain or for their relationship to obesity. Clearly, the epigenetic analysis of neuronal reprogramming is in its infancy, particularly as it impacts hippocampal controls over eating behavior.
Related Chapter 14, Epigenomic Factors in Human Obesity
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