Epigenetics & Maternal Adiposity
Creating a Cycle of Obesity
Tonya Moore
UTSPH Dietetic Intern
Created For UT WIC
Spring 2015
Creating New Life
DNA: Blueprint
Maternal environment:
Foundation
Developmental Origins of Health & Disease
• Barker’s Hypothesis: Gestational under nutrition = heart disease later
in life.
• DOHaD: expands concept to include ALL environmental interactions.
• Development is placid altered by all our exposures
• Epigenetics – process of gene expression
Barker, D. J. P. (2007). The origins of the developmental origins theory.
Journal of Internal Medicine, 261(5), 412-417. doi:10.1111/j.13652796.2007.01809.x
Epigenetics
Signals controlling which genes are
expressed & which are inactive
Expression occurs at different stages
Methylation – inactivates genes
Histone – Surface changes affect gene access
Gene Expression during female life cycle
Development 12 genes
changes
Fertilization/impl
antation -4
induced
embryotic
development- 5
induced
Gestation - 3
repressed
Childhood adolescence 14 genes
infancy - 1
(breastfeeding
induced)
Childhood - 4
induced, 1
repressed (by
abuse)
Adolescence - 6
induced, 2
repressed
adult - 1 induced
Pregnancy - 3
induced (1 by
cesarean), 1
repressed
Menopause - 2
induced, 4
repressed
General aging - 5
repressed
age-related
diseases - 3
repressed
Cancer - *2 types
of oncogenes
induced, 1 gene
repressed
Adulthood - 11
genes
Elderly - 11*
genes
For more details see reference (Csoka, A. B., Kanherkar, R. R., & Bhatia-Dey, N. 2014)
Image: Csoka, A. B., Kanherkar, R. R., & Bhatia-Dey, N. (2014). Epigenetics across the human lifespan. Frontiers in
Cell and Developmental Biology, 2(49), figure 1
Persistent Organic Pollutants (POPs)
• Toxic chemicals transported by wind &
water
• Insecticides or industrial by-products
• Stored in adipose tissue
•
•
•
•
Alters adipose tissue functions
Leads to obesity & lipotoxicity
Increases Inflammation
DM, hypertension, CVD
Image: http://www.quantumday.com/2012/06/sfrp5molecule-identified-as-factor-in.html
Endocrine Disrupting Chemicals (EDCs)
Alter signaling hormones
Activation dependent on dose, timing of exposure &
trigger
Approx. 900 chemicals
Many: POPs, plastics, phthalates
(plastic softeners), fungicides, &
pharmaceuticals
Obesogens
• Chemicals linked to increasing the risk of obesity
• 20 known chemicals
• Phthalates & Bisphenol A (BPA), Tributyltins (TBT), & Pesticides
Image: Csoka, A. B., Kanherkar, R. R., & Bhatia-Dey, N. (2014). Epigenetics across the human lifespan. Frontiers in
Cell and Developmental Biology, 2(49), figure 1
Intestinal Microbiota
• Brain Gut Connection
Energy balance, autoimmune
function, mood disorders
• Bacteroides & Prevotella
weight promoting
Intestinal Microbiota of Infants
• Vaginal vs C-section
• Breast feeding vs. Formula feeding
• BF – Less diverse, > beneficial types
• FF – More diverse, < beneficial types
Image: Csoka, A. B., Kanherkar, R. R., & Bhatia-Dey, N. (2014). Epigenetics across the human lifespan. Frontiers in
Cell and Developmental Biology, 2(49), figure 1
Environment of Malnutrition
• Under nutrition = infections &
acute disease
• Over nutrition = obesity &
chronic diseases
• Excess alcohol = displaced
nutrient absorption & liver
disease
Nutrition During Pregnancy
Disease State
U-shaped
too little or
too much
Healthy State
Underweight
Overweight
Ecological studies of Famines and Pregnancy
Dutch 1944-1945
EG: CHD, lipids, clotting, obesity
MG: respiratory, microalbuminuria
LG: impaired glucose tolerance
China 1959-1961
Metabolic syndrome, schizophrenia
Nigeria 1968-1970
Impaired glucose tolerance, HTN
Obesity & Excess Weight Gain in Pregnancy
• Over nutrition major concern
• 2010 PNSS: WIC clients
• 53.4% PP BMI >25
• 48% gained more than recommended
• Maternal complications
• GDM
• Delivery complications
• Breastfeeding difficulties
Digestion in Pregnancy: CHO
Normal weight pregnancy:
• Insulin resistance increases in 2nd trimester
• 50% - 70% reduction in insulin sensitivity
Digestion in Pregnancy: CHO
Obese pregnancy:
• IR likely present from conception
• Blood glucose levels higher
• Higher leptin & insulin levels
Digestion in Pregnancy: FFA
Normal weight pregnancy
• 1st & 2nd trimester: Hyperlipidemia & lipogenesis
• 3rd trimester: lipolysis
Digestion in Pregnancy: FFA
Obese pregnancy:
• Increased hyperlipidemia throughout
• Hepatic lipotoxicity more likely
Digestion in Pregnancy: Amino Acids
Normal weight pregnancy:
• Protein synthesis increases
• Decrease in amino acid oxidation
Obese pregnancy:
Protein synthesis may not be activated
Placenta
Nutrients & oxygen
Endocrine & metabolic
functions
Maternal blood nutrient
concentration = size and
efficiency
Image: Escudero, C., Marcelo González, Acurio, J., Valenzuela, F., & Sobrevia, L. (2013). The role of placenta in the fetal programming
associated to gestational diabetes.
Other changes due to maternal obesity
• ↑ in Cytokines
• ↑ in inflammation
• ↑ chronic stress =
↑cortisol = ↓ placental
enzyme
Image: Aml, M. E. (2012). Glucocorticoids: Biochemical group that play key role in fetal programming of adult disease. Figure 6
Child Disorders Linked to Maternal Weight
Macrosomia
Neonatal death
Overweight/obesity in childhood & adulthood
Cardiometabolic risk factors
Metabolic syndrome
Lipotoxicity
Diabetes
Asthma/wheezing
Migranes
ADHD
Autism spectrum disorders
Infant and Childhood Obesity
• Excess weight gain = macrosomia = high BMI at 1 year
• ↑ glucose levels = ↑macrosomia
• Dysfunctional adipoinsular axis
• 3.8 X’s more likely if mom is obese
• 2.5 X’s more likely if dad is obese
Glucose Intolerance / Diabetes in Children
• Smaller pancreas, less beta cells, lower insulin levels
• Native Americans GDM & T2DM children
Maternal HFD in animal studies
• Mitochondrial DNA changes = IR
• Liver & abdominal fat accumulation
• Hyperleptinemic
• Cardiac hypertrophy & contractile defect
• Increase metabolic syndrome in male offspring via changes in gene
expression & circulating cytokines.
Migraines & Overweight children
• Correlated
• Common pathways & proteins
• Increased cytokines
• Low serotonin
• Increased inflammation due to
low leptin & orexin levels
• Decrease PA exasperates
situation
Asthma & Obesity
• Obese 3 yr olds 2Xs more likely to have asthma
• Overweight boys 1.3Xs more likely
• High maternal BMI correlation & lower cortisol
levels in pregnancy
Behavioral Disorders
• 67% more likely to have autism spectrum disorder
• More likely to have ADHD symptoms
• Difficulties regulating emotions
Summary
Developmental Origins of Health and Disease & Epigenetics
Chemical exposures – POPS → EDC’s → Obesogens
Microbes
Maternal under & over nutrition
Obese vs non-obese pregnancy Macronutrients & placenta
Effects on children: obesity, diabetes, asthma, migraines, behavior
References
Aml, M. E. (2012). Glucocorticoids: Biochemical group that play key role in fetal programming of adult disease. Figure 6
Arsenescu, V., Arsenescu, R. I., King, V., Swanson, H., & Cassis, L. A. (2008). Polychlorinated biphenyl-77 induces adipocyte
differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis. Environmental Health
Perspectives, 116(6), 761-768. doi:10.1289/ehp.10554
Barker, D. J. P. (2007). The origins of the developmental origins theory. Journal of Internal Medicine, 261, 412-417.
doi:10.1111/j.1365-2796.2007.01809.x
Barouki, R., Gluckman, P. D., Grandjean, P., Hanson, M., & Heindel, J. J. (2012). Developmental origins of non-communicable
disease: Implications for research and public health. Environmental Health : A Global Access Science Source, 11, 42-069X-1142. doi:10.1186/1476-069X-11-42
Benatti, R. O., Melo, A. M., Borges, F. O., Ignacio-Souza, L. M., Simino, L. A. P., Milanski, M., . . . Torsoni, A. S. (2014). Maternal
high-fat diet consumption modulates hepatic lipid metabolism and microRNA-122 (miR-122) and microRNA-370 (miR-370)
expression in offspring. The British Journal of Nutrition, 111(12), 2112-2122. doi:10.1017/S0007114514000579
Bhandari, R., Xiao, J., & Shankar, A. (2013). Urinary bisphenol A and obesity in US children. American Journal of Epidemiology,
177(11), 1263-1270. doi:10.1093/aje/kws391
Burgueño, A. L., Cabrerizo, R., Gonzales Mansilla, N., Sookoian, S., & Pirola, C. J. (2013). Maternal high-fat intake during
pregnancy programs metabolic-syndrome-related phenotypes through liver mitochondrial DNA copy number and
transcriptional activity of liver PPARGC1A. The Journal of Nutritional Biochemistry, 24(1), 6-13.
doi:10.1016/j.jnutbio.2011.12.008
Csoka, A. B., Kanherkar, R. R., & Bhatia-Dey, N. (2014). Epigenetics across the human lifespan. Frontiers in Cell and
Developmental Biology, 2(00049) doi:10.3389/fcell.2014.00049
Dabelea, D., & Crume, T. (2011). Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes,
60(7), 1849-1855. doi:10.2337/db11-0400
References Cont.
Dalenius, K., Brindley, P., Smith, B., Reinold, C., & Grummer-Strawn, L. (2012). Pregnancy nutrition surveillance 2010 report.
Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.
Escudero, C., Marcelo González, Acurio, J., Valenzuela, F., & Sobrevia, L. (2013). The role of placenta in the fetal
programming associated to gestational diabetes.
Foster, J. A., & McVey Neufeld, K. A. (2013). Gut-brain axis: How the microbiome influences anxiety and depression. Trends in
Neurosciences, 36(5), 305-312. doi:10.1016/j.tins.2013.01.005
Gaillard, R., Steegers, E. A., Duijts, L., Felix, J. F., Hofman, A., Franco, O. H., & Jaddoe, V. W. (2014). Childhood cardiometabolic
outcomes of maternal obesity during pregnancy: The generation R study. Hypertension, 63(4), 683-691.
doi:10.1161/HYPERTENSIONAHA.113.02671
Higgins, L., Greenwood, S. L., Wareing, M., Sibley, C. P., & Mills, T. A. (2011). Obesity and the placenta: A consideration of
nutrient exchange mechanisms in relation to aberrant fetal growth. Placenta, 32(1), 1-7.
doi:http://dx.doi.org.www5.sph.uth.tmc.edu:2048/10.1016/j.placenta.2010.09.019
La Merrill, M., Emond, C., Kim, M. J., Antignac, J.-P., Le Bizec, B., Clément, K. Barouki, R. (2013). Toxicological function of
adipose tissue: Focus on persistent organic pollutants<br />. Environmental Health Perspectives, 121(2), 162-169.
doi:10.1289/ehp.1205485
Larqué, E., Parrilla, J. J., Koletzko, B., Pagán, A., Prieto, M. T., Blanco, J. E., . . . Demmelmair, H. (2014). Placental fatty acid
transfer: A key factor in fetal growth. Annals of Nutrition & Metabolism, 64(3-4), 247.
Lausten-Thomsen, U., Bille, D. S., Nässlund, I., Folskov, L., Larsen, T., & Holm, J. (2013). Neonatal anthropometrics and
correlation to childhood obesity--data from the danish children's obesity clinic. European Journal of Pediatrics, 172(6), 747751. doi:10.1007/s00431-013-1949-z
O'Reilly, J. R., & Reynolds, R. M. (2013). The risk of maternal obesity to the long-term health of the offspring. Clinical
Endocrinology, 78(1), 9-16. doi:10.1111/cen.12055
References Cont.
Osgood, N. D., Dyck, R. F., & Grassmann, W. K. (2011). The inter- and intragenerational impact of gestational diabetes on the
epidemic of type 2 diabetes. American Journal of Public Health, 101(1), 173-179. doi:10.2105/AJPH.2009.186890
Patricia M Vuguin, Yoshinori Seki, Ellen B Katz, Maureen J Charron, Kirsten Hartil, Michael Kruse, . . . Lyda Williams. (2013).
Shared effects of genetic and intrauterine and perinatal environment on the development of metabolic syndrome: e63021.
PLoS One, 8(5) doi:10.1371/journal.pone.0063021
Ravid, S. (2014). Migraine & paediatric obesity: A plausible link? The Indian Journal of Medical Research, 139(3), 343.
Roberts, K. A., Riley, S. C., Reynolds, R. M., Barr, S., Evans, M., Statham, A., . . . Denison, F. C. (2011). Placental structure and
inflammation in pregnancies associated with obesity. Placenta, 32(3), 247-254.
doi:http://dx.doi.org.www5.sph.uth.tmc.edu:2048/10.1016/j.placenta.2010.12.023
St Clair D, Xu M, Wang P,et al. (2005). RAtes of adult schizophrenia following prenatal exposure to the chinese famine of
1959-1961 doi:10.1001/jama.294.5.557
Suglia, S. F., Chambers, E. C., Rosario, A., & Duarte, C. S. (2011). Asthma and obesity in three-year-old urban children: Role of
sex and home environment. The Journal of Pediatrics, 159(1), 14-20.e1.
doi:http://dx.doi.org.www5.sph.uth.tmc.edu:2048/10.1016/j.jpeds.2011.01.049
Thompson, A. L. (2012). Developmental origins of obesity: Early feeding environments, infant growth, and the intestinal
microbiome. American Journal of Human Biology : The Official Journal of the Human Biology Council, 24(3), 350-360.
doi:10.1002/ajhb.22254
Turdi, S., Ge, W., Hu, N., Bradley, K. M., Wang, X., & Ren, J. (2013). Interaction between maternal and postnatal high fat diet
leads to a greater risk of myocardial dysfunction in offspring via enhanced lipotoxicity, IRS-1 serine phosphorylation and
mitochondrial defects. England: Elsevier B.V. doi:10.1016/j.yjmcc.2012.12.007
U.S. Food and Drug Administration. (2014). Bisphenol A (BPA): Use in food contact application. Retrieved from
http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm064437.htm
References Cont.
United States Environmental Protection Agency. (2009). Persistent organic pollutants: A global issue, A global response.
Retrieved from http://www2.epa.gov/international-cooperation/persistent-organic-pollutants-global-issue-global-response
Valvi, D., Mendez, M. A., Martinez, D., Grimalt, J. O., Torrent, M., & Sunyer, J.: Martine Vrijheid, M. (2012). Prenatal
concentrations of polychlorinated biphenyls, DDE, and DDT and overweight in children: A prospective birth cohort study.
Environ Health Perspect, 120, 451-457. doi:http://dx.doi.org/10.1289/ehp.1103862
Williams, S. C. (2013). Epigenetics. Proceedings of the National Academy of Sciences of the United States of America, 110(9),
3209. doi:10.1073/pnas.1302488110
Wright, R. J., Fisher, K., Chiu, Y. M., Wright, R. O., Fein, R., Cohen, S., & Coull, B. A. (2013). Disrupted prenatal maternal
cortisol, maternal obesity, and childhood wheeze: Insights into prenatal programming. American Journal of Respiratory and
Critical Care Medicine, 187(11), 1186-93.
Zhang, L., Long, N. M., Hein, S. M., Ma, Y., Nathanielsz, P. W., & Ford, S. P. (2011). Maternal obesity in ewes results in reduced
fetal pancreatic β-cell numbers in late gestation and decreased circulating insulin concentration at term. Domestic Animal
Endocrinology, 40(1), 30-39. doi:10.1016/j.domaniend.2010.08.004