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Epigenetics of Eating Disorders

Journal Club: February 9, 2011
by

Stephanie Zerwas

on 15 March 2011

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Transcript of Epigenetics of Eating Disorders

Epigenetics of Eating Disorders 1. Eating Disorders AN: obstetric complications, childhood feeding and sleeping problems, physical exercise, overanxious parenting, OCDP, perfectionism
Risk Factors Heritability + GxE BN: obstetric complications, dieting, childhood + parental obesity, alchoholism, pubertal timing, sexual abuse, negative self-evaluation BED: Childhood obseity, family overeating, high parental demands, negative affect, parental mood and substance abuse, perfectionism, Heritable

Genes: small effect sizes

Missing heritability? GxE
Little known

Epigenetic Processes

Evolutionary Pressure: negative selection for AN
Disapear from gene pool?
Rare genetic changes recent origin
Enviornmentally induced epigenetic changes
2. Epigenetics Epigenetic mechanisms: regulate gene expression independent of DNA sequence a. DNA Methylation - methyl groups tag DNA and activate or repress genes. b. Histone Modification -Binding of epigenetic factors to histone "tails";
alters the extent to which DNA is wrapped around histones and the
availability of genes in the DNA to be activated. c. Small interfereing RNA (siRNA) - suppress activity via RNA interference
(RNAi) Timing Perinatal period Metastable epialleles - loci range of
phoenotypes from identical cells Peripubertal epigenetic changes
sex hormones alter DNA methylation Experience: calorie restriction alters
fat cell DNA methylation Transgenerational

Meiotic transmission

Evidence:
Paternal smoking - higher BMI in male offspring
Pregnant women during Dutch famine- reduced
birthweights in grandchildren MZ discordance? Developmental Origins of Disease Hypothesis (DOHAD)
(also called fetal programming)
In utero exposure to poor enviornment during critical windows causes initially adaptive changes in biology but ultimately leads to mismatch with environment and increased risk for disease 3. Maternal Stress During Pregnancy Eating Disorders Fetal glucocorticoid exposure fetal growth retardation
obesity
anxiety
inflammation
HPA malfunction Animal model lack of postnatal care - stress phenotypes in offspring
epigenetic modification Maternal stress
increased susceptibility to chronic disease increased anxiety overall
pregnancy - more anxious
gestational weight gain concerns
BN - more anxiety and depression

Stressful life events early in life increase
risk for eating disorder. Through epigenetic
changes?

Possible interventions at pregnancy
Improve nutrition
Reduce glucocorticoids Dutch Famine food deprivation - in utero effects

factors:
timing of exposure
gender of offspring

Overall
8 kg heavier in adulthood

Eating Disorders in Pregnancy Early exposure:
greater adult obestiy
increased heart disease
CNS abnormalities
schizophrenia
addictions Early to mid exposure & male:
Increased anti-social personality
disorder Mid to late exposure & male:
Increased affective disorder Eating Disorder Implications Maternal undernutrition in pregnancy
increased risk of obesity and behavioral problems

Maternal and paternal obesity during pregnancy
? Animal Models Less methylation of IGF2 (insulin like growth factor) gene - 6 decades later 4. Nutrition during Pregnancy Poorer birth outcomes
Fetal growth
Low pre-pregnancy BMI
Altered eating during pregnancy Adaptive:
Exposed women:
Short term - more reproductive sucess
Early Menarche
Dietary manipulation:
agouti viable yellow allele - prevents transgenerational amplification of obesity
Methyl donors - reduce kinky tail phenotype
Low availability of methyl donors linked to hypomethylation and cancer
Methyl donors include mincronutrients - B2, B6, B12, folate, methionine, and choline 5. Candidate Genes FTO 2 copies of risk allele - 70% increase risk of obesity
Associated with increased BMI
Enhanced by lack of physical activity
Expressed in hypothalamus
Increased FTO activity - increase DNA demethylation
Early changes - set resting energy expenditure?
Environmentally sensitive throughout life? Leptin & Receptor Peptide: energy storage and utilization
Polymorphisms associated with:
birth weight
metabolic diseases
Potential loci for modification
Leptin
Transport system across BBB
Receptor
Developmental
Involved in neuronal migration
survival
outgrowth
Set point for energy homeostasis? POMC Polypeptide hormone precursor
Changes in methylation associated with underweight
Increased methylation - increase alcohol craving BDNF Affects neural development
Regulates neuronal histone -
act epigenetically through histone modification?
Social defeat stress
Alters regulation of BDNF through histone mod 6. Psychological Processes Pathological Fear Conditioning Emotion circuitry sensitive to environmental plasticity
Long-term memory formation and fear conditioning
Epigenetic control

Cognitive function
Affected by epigenetic changes

Psychological Intervention
Mediated by epigenetic changes?
7. Epigenetic Research and Eating Disorders
DNA hypomethylation found in lymphocytes in AN
decreased expression of SCNA gene

DNA hypermethylation of ANP gene promoter in BN
Lower levels of ANP (atrial natriuretic peptide) in eating disorders

Changes: Dopaminergic genes and POMC gene
Methylation Patterns: Evidence Research Approaches

Examine candidate genes
No

Post-mortem brain:
Confounded by cuase of death
Diversity of neural processes in eating disorders
Possible targets?
1. Cortical/Subcortical Imbalence
2. Stress Axis
3. Altered Cognitive Functions

Embryogenesis - cell replication high,

Rodent Models
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