Early-life Influences on Obesity: Pre-conception to Adolescence

Journal Articles

Weight management in transitional economies

Chiang PH, Wahlqvist ML, Lee MS, et al. Fast-food outlets and walkability in school neighbourhoods predict fatness in boys and height in girls: a Taiwanese population study. Public Health Nutr. 2011;14(9):1601-9.

Lee MS, Huang LY, Chang YH, et al. Lower birth weight and diet in Taiwanese girls more than boys predicts learning impediments. Res Dev Disabil. 2012;33(6):2203-12.

Lee MS, Huang YC, Su HH, et al. A simple food quality index predicts mortality in elderly Taiwanese. J Nutr Health Aging. 2011;15(10):815-21.

Siahpush M, Huang TT, Sikora A, et al. Prolonged financial stress predicts subsequent obesity: results from a prospective study of an Australian national sample. Obesity. 2014;22(2):616-621.

Wahlqvist ML. Ecosystem health disorders — changing perspectives in clinical medicine and nutrition. Asia Pac J Clin Nutr. 2014;23(1):1-15.

Wahlqvist ML, Chang HY, Chen CC, et al. Is impaired energy regulation the core of the metabolic syndrome in various ethnic groups of the USA and Taiwan? BMC Endocr Disord. 2010;10(11):1-16.

Wahlqvist ML, Huang LY, Lee MS, et al. Dietary quality of elders and children is interdependent in Taiwanese communities: a NAHSIT mapping study. Ecol Food Nutr. 2014;53(1):81-97.

Wen CP, Wai JP, Tsai MK, et al. Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet. 2011;378(9798):1244-53.

Intended and unintended pregnancies

Finer LB, Zolna MR. Shifts in intended and unintended pregnancies in the United States, 2001–2008. Am J Public Health. 2014;104(Suppl 1):S43-8.

Paternal contributions: the role of RNA in sperm

Fullston T, Ohlsson Teague EM, Palmer NO, et al. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J. 2013;27(10):4226-43.

Jodar M, Selvaraju S, Sendler E, et al. The presence, role and clinical use of spermatozoal RNAs. Hum Reprod Update. 2013;19(6):604-24.

Johnson GD, Sendler E, Lalancette C, et al. Cleavage of rRNA ensures translational cessation in sperm at fertilization. Mol Hum Reprod. 2011;17(12):721-6.

Krawetz SA, Kruger A, Lalancette C, et al. A survey of small RNAs in human sperm. Hum Reprod. 2011;26(12):3401-12.

Marczylo EL, Amoako AA, Konje JC, et al. Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics. 2012;7(5):432-9.

Miller D, Tang PZ, Skinner C, Lilford R. Differential RNA fingerprinting as a tool in the analysis of spermatozoal gene expression. Hum Reprod. 1994;9(5):864-9.

Ostermeier GC, Miller D, Huntriss JD, et al. Reproductive biology: delivering spermatozoan RNA to the oocyte. Nature. 2004;429(6988):154.

Rodgers AB, Morgan CP, Bronson SL, et al. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci. 2013;33(21):9003-12.

Sendler E, Johnson GD, Mao S, et al. Stability, delivery and functions of human sperm RNAs at fertilization. Nucleic Acids Res. 2013;41(7):4104-17.

Transgenerational response to nutrition, early-life circumstances, and longevity

Bygren LO, Kaati G, Edvinsson S. Longevity determined by paternal ancestors' nutrition during their slow growth period. Acta Biotheor. 2001;49(1):53-9.

Bygren LO, Tinghög P, Carstensen J, et al. Change in paternal grandmothers' early food supply influenced cardiovascular mortality of the female grandchildren. BMC Genet. 2014;15:12.

Chen TH, Chiu YH, Boucher BJ. Transgenerational effects of betel-quid chewing on the development of the metabolic syndrome in the Keelung Community-based Integrated Screening Program. Am J Clin Nutr. 2006;83(3):688-92.

Michels KB. The promises and challenges of epigenetic epidemiology. Exp Gerontol. 2010;45(4):297-301.

Natt D, Lindqvist N, Stranneheim H, et al. Inheritance of acquired behaviour adaptations and brain gene expression in chickens. PLoS One. 2009;4(7):e6405.

Pembrey M, Saffery R, Bygren LO, et al. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J Med Genet. 2014;51(9):563-72.

Soubry A, Hoyo C, Jirtle RL, Murphy SK. A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays. 2014;36(4):359-71.

The microbiome and global health

Algert CS, McElduff A, Morris JM, Roberts CL. Perinatal risk factors for early onset of Type 1 diabetes in a 2000–2005 birth cohort. Diabet Med. 2009;26(12):1193-7.

Blustein J, Attina T, Liu M, et al. Association of caesarean delivery with child adiposity from age 6 weeks to 15 years. Int J Obes. 2013;37(7):900-6.

Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158(4):705-21.

Decker E, Engelmann G, Findeisen A, et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics. 2010;125(6):e1433-40.

Ege MJ, Mayer M, Normand AC, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011;364(8):701-9.

Hidalgo G, Marini E, Sanchez W, et al. The nutrition transition in the Venezuelan Amazonia: increased overweight and obesity with transculturation. Am J Hum Biol. 2014;26(5):710-2.

Huh SY, Rifas-Shiman SL, Zera CA, et al. Delivery by caesarean section and risk of obesity in preschool age children: a prospective cohort study. Arch Dis Child. 2012;97(7):610-6.

Littman DR, Pamer EG. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe. 2011;10(4):311-23.

Mueller NT, Whyatt R, Hoepner L, et al. Prenatal exposure to antibiotics, cesarean section, and risk of childhood obesity. Int J Obes. 2014. [Epub ahead of print]

Mukherji A, Kobiita A, Ye T, et al. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell. 2013;153(4):812-27.

Rescigno M. Gut commensal flora: tolerance and homeostasis. F1000 Biol Rep. 2009;1:9.

Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222-7.

Effects of maternal exercise before and during gestation

Borodulin KM, Evenson KR, Wen F, et al. Physical activity patterns during pregnancy. Med Sci Sports Exerc. 2008;40(11):1901-8.

Dello Russo M, Ahrens W, De Vriendt T, et al. Gestational weight gain and adiposity, fat distribution, metabolic profile, and blood pressure in offspring: the IDEFICS project. Int J Obes. 2013;37(7):914-9.

Dye TD, Knox KL, Artal R, et al. Physical activity, obesity, and diabetes in pregnancy. Am J Epidemiol. 1997;146(11):961-5.

Hochner H, Friedlander Y, Calderon-Margalit R, et al. Associations of maternal prepregnancy body mass index and gestational weight gain with adult offspring cardiometabolic risk factors: the Jerusalem Perinatal Family Follow-up Study. Circulation. 2012;125(11):1381-9.

Ludwig DS, Currie J. The association between pregnancy weight gain and birthweight: a within-family comparison. Lancet. 2010;376(9745):984-90.

Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and cardiovascular disease death: prospective evidence from the child health and development studies cohort. Hypertension. 2010;56(1):166-71.

Saftlas AF, Logsden-Sackett N, Wang W, et al. Work, leisure-time physical activity, and risk of preeclampsia and gestational hypertension. Am J Epidemiol. 2004;160(8):758-65.

Streuling I, Beyerlein A, Rosenfeld E, et al. Physical activity and gestational weight gain: a meta-analysis of intervention trials. BJOG. 2011;118(3):278-84.

Szymanski LM, Satin AJ. Exercise during pregnancy: fetal responses to current public health guidelines. Obstet Gynecol. 2012;119(3):603-10.

Szymanski LM, Satin AJ. Strenuous exercise during pregnancy: is there a limit? Am J Obstet Gynecol. 2012;207(3):179.e1-6.

Tobias DK, Zhang C, van Dam RM, et al. Physical activity before and during pregnancy and risk of gestational diabetes mellitus: a meta-analysis. Diabetes Care. 2011;34(1):223-9.

A developmental approach to childhood obesity

Bouret SG. Role of early hormonal and nutritional experiences in shaping feeding behavior and hypothalamic development. J Nutr. 2010;140(3):653-7.

Godfrey KM, Gluckman PD, Hanson MA. Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol Metab. 2010; 21:199-205.

Huang TT, Drewnosksi A, Kumanyika S, Glass TA. A systems-oriented multilevel framework for addressing obesity in the 21st century. Prev Chronic Dis. 2009;6(3):A82.

Janesick A, Blumberg B. Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity. Birth Defects Res C Embryo Today. 2011;93(1):34-50.

Koza RA, Nikonova L, Hogan J, et al. Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PLoS Genet. 2006;2(5):e81.

Nutritional influences on human developmental epigenetics

Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. 2007;104(32):13056-61.

Dominguez-Salas P, Moore SE, Baker MS, et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun. 2014;5:3746.

Rayco-Solon P, Fulford AJ, Prentice AM. Differential effects of seasonality on preterm birth and intrauterine growth restriction in rural Africans. Am J Clin Nutr. 2005;81(1):134-9.

Waterland RA, Dolinoy DC, Lin JR, et al. Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis. 2006;44(9):401-6.

Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr. 1999;69(2):179-97.

Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23(15):5293-300.

Waterland RA, Kellermayer R, Laritsky E, et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 2010;6(12):e1001252.

Wolff GL, Kodell RL, Moore SR, Cooney CA. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 1998;12(11):949-57.

Ontogeny of taste preferences

Bilkó A, Altbäcker V, Hudson R. Transmission of food preference in the rabbit: the means of information transfer. Physiol Behav. 1994;56(5):907-12.

Mennella JA, Jagnow CP, Beauchamp GK. Prenatal and postnatal flavor learning by human infants. Pediatrics. 2001;107(6):E88.

Obesigenic effects of developmental programming

Desai M, Gayle D, Babu J, Ross MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol. 2005;288(1):R91-6.

Ross MG, Desai M. Gestational programming: population survival effects of drought and famine during pregnancy. Am J Physiol Regul Integr Comp Physiol. 2005;288(1):R25-33.

Breast feeding: molecules, nutrients, and context

Baird J, Fisher D, Lucas P, et al. Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ. 2005;331(7522):929-34.

Belfort MB, Rifas-Shiman SL, Rich-Edwards J, et al. Size at birth, infant growth, and blood pressure at three years of age. J Pediatr. 2007;151(6):670-4.

Collado MC, Laitinen K, Salminen S, Isolauri E. Maternal weight and excessive weight gain during pregnancy modify the immunomodulatory potential of breast milk. Pediatr Res. 2012;72(1):77-85.

Fields DA, Demerath EW. Relationship of insulin, glucose, leptin, IL-6 and TNF-α in human breast milk with infant growth and body composition. Pediatr Obes. 2012;7(4):304-12.

Oben JA, Mouralidarane A, Samuelsson AM, et al. Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J Hepatol. 2010;52(6):913-20.

Ogden CL, Carroll MD, Flegal KM. Prevalence of obesity in the United States. JAMA. 2014;312(2):189-90.

Schueler J, Alexander B, Hart AM, et al. Presence and dynamics of leptin, GLP-1, and PYY in human breast milk at early postpartum. Obesity. 2013;21(7):1451-8.

Wahlig JL, Bales ES, Jackman MR, et al. Impact of high-fat diet and obesity on energy balance and fuel utilization during the metabolic challenge of lactation. Obesity. 2012;20(1):65-75.

Weyermann M, Brenner H, Rothenbacher D. Adipokines in human milk and risk of overweight in early childhood: a prospective cohort study. Epidemiology. 2007;18(6):722-9.

Appetite as a susceptibility factor in obesity risk

Carnell S, Haworth CM, Plomin R, Wardle J. Genetic influence on appetite in children. Int J Obes. 2008;32(10):1468-73.

Hill C, Llewellyn CH, Saxton J, et al. Adiposity and 'eating in the absence of hunger' in children. Int J Obes. 2008;32(10):1499-505.

Jaarsveld CH van, Boniface D, Llewellyn CH, Wardle J. Appetite and growth: a longitudinal sibling analysis. JAMA Pediatr. 2014;168(4):345-50.

Llewellyn CH, van Jaarsveld CH, Johnson L, et al. Nature and nurture in infant appetite: analysis of the Gemini twin birth cohort. Am J Clin Nutr. 2010;91(5):1172-9.

Schachter S. Obesity and eating. Internal and external cues differentially affect the eating behavior of obese and normal subjects. Science. 1968;161(3843):751-6.

Wardle J, Guthrie CA, Sanderson S, Rapoport L. Development of the Children's Eating Behaviour Questionnaire. J Child Psychol Psychiatry. 2001;42(7):963-70.

Exercise, neurodegeneration, and FNDC5/irisin

Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108(7):3017-22.

Marosi K, Mattson MP. BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab. 2014;25(2):89-98.

Mustroph ML, Chen S, Desai SC, et al. Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience. 2012;219:62-71.

Praag H van, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2(3):266-70.

Voss MW, Prakash RS, Erickson KI, et al. Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front Aging Neurosci. 2010;2. eCollection 2010.

Wrann CD, White JP, Salogiannnis J, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649-59.

Urban adolescent fitness for the next generation

Ewing R, Meakins G, Hamidi S, Nelson AC. Relationship between urban sprawl and physical activity, obesity, and morbidity — update and refinement. Health Place. 2014;26:118-26.

Huotari P, Nupponen H, Mikkelsson L, et al. Adolescent physical fitness and activity as predictors of adulthood activity. J Sports Sci. 2011;29(11):1135-41.

Jongeneel-Grimen B, Droomers M, van Oers HA, et al. The relationship between physical activity and the living environment: a multi-level analyses focusing on changes over time in environmental factors. Health Place. 2014;26:149-60.

Rizzo NS, Ruiz JR, Hurtig-Wennlöf A, et al. Relationship of physical activity, fitness, and fatness with clustered metabolic risk in children and adolescents: the European youth heart study. J Pediatr. 2007;150(4):388-94.

Ruiz JR, Rizzo NS, Hurtig-Wennlöf A, et al. Relations of total physical activity and intensity to fitness and fatness in children: the European Youth Heart Study. Am J Clin Nutr. 2006;84(2):299-303.

Websites and Reports

American College of Obstetricians and Gynecologists, Committee on Adolescent Health Care Long-Acting Reversible Contraception Working Group. Adolescents and long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol. 2012;120(4):983-9.

Centers for Disease Control and Prevention. Overweight and Obesity: Data and Statistics. Obesity Prevalence Maps. 2013.

Centers for Disease Control and Prevention (CDC). Physical activity levels among children aged 9–13 years — United States, 2002. MMWR Morb Mortal Wkly Rep. 2003;52(33):785-8.

Cities Changing Diabetes
A partnership of University College London, Steno Diabetes Center, and Novo Nordisk to combat urban diabetes.

EPODE European Network
An alliance aiming to prevent childhood obesity in Europe by raising political awareness, sharing knowledge, and facilitating development of community-based interventions.

Organisation for Economic Cooperation and Development (OECD). Obesity Update. June 2014.

Rasmussen KM, Yaktine AL, eds. Institute of Medicine (U.S.) and National Research Council (U.S.) Committee to Reexamine IOM Pregnancy Weight Guidelines. Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC: National Academies Press (U.S.); 2009.

Trust for America's Health, Robert Wood Johnson Foundation. F as in Fat: How obesity threatens America's future. 2012.

U.S. Department of Health and Human Services. Office of Disease Prevention and Health Promotion. Physical Activity Guidelines for Americans. 2008.

Sponsors

Presented by

Rates of overweight and obesity have skyrocketed in the past three decades in many parts of the world and in all age groups. These chronic conditions increase risk of death as well as diabetes, heart disease, and certain cancers. According to the World Health Organization, 35% of adults were overweight in 2008 and another 11% were obese. There were 40 million overweight or obese children under age 5 in 2012.

Our modern environment plays a clear role in the increasing prevalence of obesity, as do genetic and epigenetic influences transmitted from parent to child. The conference explored numerous etiological factors predisposing to obesity and related chronic metabolic diseases. Such factors include the stress of living in transitional economies or diverse societies and the obesifying effects of antibiotic use, which reduces microbial diversity.

The conference focused on environmental exposures that occur in the earliest stages of life. The period from gestation through age 3 is regarded as a critical time for determining obesity outcomes. After birth, neurons involved in appetite and satiety continue to develop, representing a window when interventions could be particularly effective.

It is also important to study maternal fitness before and during pregnancy. Yet the speakers emphasized that mothers must not be blamed for childhood obesity. Several talks explored how the nutritional status of mothers and fathers before conception, the stress they experience, and even the experiences of their parents, could influence a child's obesity risk. Researchers think these effects are mediated through epigenetics, which are modifications to gene expression that do not affect the DNA sequence and can be heritable.

In the session devoted to pre-conception and generational effects of nutrition, Mark L. Wahlqvist made the case that where we live affects obesity risk and Maria Gloria Dominguez-Bello discussed the impact of urbanization on obesity rates. Lawrence B. Finer discussed the impact of unintended pregnancy. Stephen A. Krawetz explored paternal influences on obesity, particularly through RNA delivered to the oocyte at fertilization. A panel discussion moderated by John G. Kral further explored harmful early-life exposures and looked at efforts to reverse obesity trends. Linda M. Szymanski described how physical activity could reduce the adverse pregnancy outcomes of gestational weight gain, gestational diabetes, and preeclampsia.

In the session on intrauterine environment and programming, Shari Barkin described an upcoming IOM conference that will look at external environment, nutrition, and development in early life. Robert A. Waterland explained an epigenetic effect called metastable epialleles, and Michael G. Ross and Mina Desai discussed rat models that support the importance of the intrauterine environment in childhood obesity. Julie A. Mennella discussed the impact of eating habits established early in life, followed by Nancy F. Krebs, who described the importance of infant diet in the 6 months after birth.

In the final session, which explored interventions, Christiane Wrann talked about the potential for exercise to act as a mechanism for resetting brain function, and Susanne Stormer described some of the efforts underway at Novo Nordisk, a Copenhagen-based company, to combat the diabetes epidemic. Finally, Nico S. Rizzo presented discouraging data on physical fitness in children and adolescents in view of the known benefits of physical activity in reducing obesity among adolescents.

The meeting was conceived by the Sackler Institute's Obesity, Diabetes, and Nutrition-related Diseases Working Group, which includes researchers from academia, industry, and nonprofit groups. Executive Director Mandana Arabi urged anyone with expertise in this area who is interested in getting involved to contact the institute.

Gestation and the first few years of life represent a highly plastic period when it may be possible to modulate environmental exposures and reduce obesity risk. (Image courtesy of Shari Barkin)

Highlights

Built environments can be designed to facilitate walking and to promote safety and dietary diversity.

Women who have unintended pregnancies are less likely to obtain adequate prenatal care or to breastfeed.

Sperm cells deliver many types of RNA to the oocyte during fertilization, some of which may be involved in metabolism.

Changes in nutritional status during critical periods before puberty could affect health and longevity in subsequent generations.

Weight management in transitional economies

Mark L. Wahlqvist of Zhejiang University, China, began by making the case that where we live affects obesity risk. As is well known, high agricultural productivity tends to correlate with high rates of obesity. Financial insecurity can also affect obesity rates; an Australian study, for example, associated stress during the global financial crisis of 2008 with increased obesity risk. But economic factors cannot fully explain obesity trends. For example, obesity has increased more in the past several decades in the U.S. and Mexico than in other countries with similar levels of economic development, such as France, Italy, and Korea.

The built environment also plays a role in obesity rates, and Wahlqvist argued we should change the way we interact with it. A cohort study by his colleague found a reduced risk of death among adults in Taiwan who walked for 15 minutes every day (about half the amount of exercise currently recommend by the World Health Organization). Jogging or running lowered the risk further. However, built areas that offer the option to walk are becoming less common, especially in areas that are under economic pressure to expand urban development, Wahlqvist explained. It is also important to consider how cities are developed. Wahlqvist and colleagues found an association between a high density of fast-food stores and higher BMI among boys in Taiwan aged 6–13 years old.

Some countries have made progress in reducing obesity among children through efforts including changing the environment and increasing awareness of healthy diets and lifestyles. One example is the EPODE European Network, a community-based intervention program that targets children aged up to 12 years old. The program began in France and is now operating in many countries. Among the study's goals is to encourage families and children to exercise and follow healthy diets. The program relies on the participation of politicians, town planners, health groups, teachers, journalists, and sociologists. Wahlqvist stressed the importance of community support for EPODE and similar programs. In France, obesity rates among children aged 3–17 years old have stabilized in the past 30 years. Wahlqvist attributed part of this success to the EPODE program.

Obesity rates are higher in the U.S. and Mexico than in countries with similar economic development, such as France and Korea. (Image courtesy of Mark L. Wahlqvist)

Intended and unintended pregnancies

Lawrence B. Finer of the Guttmacher Institute talked about the impact of unintended pregnancies on the health of mothers and infants. Mothers who have unintended pregnancies are less likely to obtain adequate prenatal care or to breastfeed their babies. Finer presented recent U.S. data showing 14% of births were from pregnancies that women did not want and 26% were from mistimed pregnancies (women wanted to get pregnant at a different time). The rate of unintended pregnancy in the U.S. increased between 1994 and 2008.

Finer suggested this trend could be due in part to shifting demographics, with higher representation of groups that tend to have more unintended pregnancies, such as women living with a partner, Hispanic women, and women with low income or education levels. Among low-income and less educated women, who have historically carried a disproportionate burden of unintended pregnancies, the rates are increasing. However, Finer is hopeful that data from recent years (which will soon be available) will show unintended pregnancy declining as more women start using highly effective contraceptive methods, such as intrauterine devices (IUDs).

Paternal contributions: the role of sperm RNA

Stephen A. Krawetz of Wayne State University School of Medicine explored paternal influence on early embryonic metabolism, particularly through RNA delivered to the oocyte from the sperm. His team has identified many classes of RNA molecules in sperm cells. Although sperm RNA has generally been assumed to be less important than oocyte RNA because it is much less abundant, these RNA molecules have begun to be recognized in the past 10 years for their many possible roles in embryogenesis.

Similar to somatic cell RNA, about 89% of sperm cell RNA is ribosomal. Another 5% is mitochondrial and the remaining 6% comprises coding RNAs, long and short noncoding RNAs, repetitive sequences, and intronic, exonic, and intergenic elements. Many of the coding RNAs, or transcripts, are thought to code for proteins involved in male fertility, such as integrator complex subunit 1 (INTS1). Krawetz and his team have focused on a class of small noncoding RNAs called microRNAs, or miRNAs. The sperm delivers many miRNAs to the oocyte. The most abundant, miR-34c, is required for cell division. Several others are involved in establishing early metabolism. Two, miR-375 and miR-192, are involved in insulin sensitivity and resistance, respectively.

Recent studies suggest that factors such as stress, obesity, and smoking alter the miRNA content of sperm. These findings raise the possibility that environmental cues leave marks on the male gamete that may affect how the offspring responds to its environment.

Some of the abundant microRNAs that sperm cells deliver to oocytes during fertilization have been implicated in insulin response and metabolism. (Image courtesy of Stephen A. Krawetz)

Grandparents leave marks

Nico S. Rizzo of Loma Linda University and the Karolinska Institute discussed how grandparents can influence the health of their grandchildren. Rizzo's mentor and collaborator Lars Olov Bygren conducted one of the first studies on the association between grandparent nutrition and grandchild longevity. The study included grandparents born in the early 1900s in Överkalix parish in northern Sweden and measured nutrition based on harvest records and other documents. Poor nutrition among paternal grandfathers during their slow growth period (the 3 years before puberty) was associated with increased longevity in their grandsons. In contrast, paternal grandfathers who had abundant food in this period tended to have grandsons with shorter lives. A similar relationship was observed between paternal grandmothers and granddaughters. As Rizzo pointed out during the panel discussion, the phenomenon seems to be independent of obesity, which has a very low prevalence in Sweden.

The mechanisms underlying the results seen in the Överkalix study are not clear. One possibility is that the gamete cells of the grandparents underwent epigenetic changes in response to fluctuations in nutritional status. Rizzo presented recent data suggesting that this variation could impact offspring health. Women had a higher risk of death if their paternal grandmothers went from having poor to good, or good to poor, food availability during childhood, compared to those whose grandmothers experienced consistent food availability. Rizzo and his colleagues are now conducting studies in Sweden and the U.S. to look at the impact on children of the nutrition of their great- and great-great-grandparents.

Highlights

Westernization is associated with loss of microbiome diversity.

Exercise during pregnancy could reduce gestational weight gain and diabetes, as well as obesity risk in children.

Use of highly effective long-acting contraceptive methods, such as IUDs and implants, could reduce the rate of unintended pregnancy in the U.S., which is relatively high compared to other developed countries.

It may soon be possible to assess RNA damage in sperm and reverse or minimize the damage.

There may be critical windows in childhood when nutritional status exerts transgenerational effects that could be targeted to reduce obesity risk.

Modernizing the microbiome

The greatest rises in obesity rates in the last several decades have been in countries that have highly diverse populations (such as the U.S.) or middle-tier economies (such as Brazil). Maria Gloria Dominguez-Bello of New York University School of Medicine suggested the high burden of obesity in these areas could be partly due to urbanization. She found that BMI increased as people moved from the remote jungle village of Checherta in the Amazon to a town in Peru and a city in Brazil.

Dominguez-Bello stressed that people in Checherta are not malnourished or disadvantaged, and despite lacking basic medicines such as antibiotics, tend to be very healthy. Many changes occur with relocation to urban areas. People often experience dietary changes and poorer air quality. They usually have improved access to medicine but become more sedentary and have less contact with family and nature. Dominguez-Bello thinks it likely that the microbiome changes as well.

As a result of the use and overuse of antibiotics in urban environments, mothers may not have vaginal lactobacillus and bifidobacteria, which babies usually acquire during delivery and which are thought to train the early immune system and help reduce the risk of inflammation and autoimmune disorders. In fact, Dominguez-Bello and her colleagues at Columbia University recently reported that higher rates of childhood obesity in a cohort of African American and Dominican families in New York City were associated with use of antibiotics during pregnancy or cesarean delivery, during which babies do not acquire vaginal microbes. Several studies have also linked C-sections to higher rates of asthma, type 1 diabetes, and celiac disease.

However, according to Dominguez-Bello, it is difficult to understand the impact of cesarean delivery and antibiotic use on obesity and other chronic diseases in the U.S. because our microbiomes were probably altered long ago. Indeed, inhabitants of U.S. cities have only about 75% of the gut bacterial diversity found in rural populations in Malawi and the Venezuelan Amazon. The goal now is to understand which lost species are important in early life, such as the first days after birth. "There is still a lot of potential for microbiome restoration if we can understand [this] and then [reduce] the risk of diseases for that baby later on," Dominguez-Bello said.

People in U.S. cities (blue dots) have less-diverse gut microbiomes than Amerindians (green dots) and Malawians (red dots). (Image courtesy of Maria Gloria Dominguez-Bello)

Maternal exercise and infant outcomes

Linda M. Szymanski of Johns Hopkins University School of Medicine focused on how physical activity may affect three pregnancy outcomes: excess gestational weight gain (GWG), gestational diabetes (GDM), and preeclampsia (PEC). These conditions are linked to delivery complications and occur at higher rates in mothers who are overweight before becoming pregnant. Preeclampsia is also linked to preterm delivery. Women with GDM and excessive GWG tend to have heavier babies whose obesity risk is higher in adolescence and even adulthood.

Although most studies indicate that physical activity can reduce GWG, GDM, and PEC, the evidence could be stronger. Nevertheless, there are strong data suggesting exercise before or during pregnancy reduces GDM risk. The American Diabetes Association now recommends exercise to help control GDM when diet alone is not enough. Studies also suggest physical activity can limit GWG and should be used in conjunction with other approaches. Finally, although small studies suggest physical activity could reduce PEC, Szymanski said that concerns remain among physicians about the "theoretical" idea that exercise may reduce blood flow to the placenta in hypertensive women. Nonetheless, in 2013 the American College of Obstetrics and Gynecologists recommended that hypertensive women who exercised before pregnancy should continue moderate exercise if their blood pressure remained controlled.

The children of women who have the greatest gestational weight gain face higher obesity risk as adults. (Image courtesy of Linda M. Szymanski)

Exercise during pregnancy could help reduce the risk of gestational diabetes in women with high BMI. (Image courtesy of Linda M. Szymanski)

Panel discussion: understanding harmful exposures and reversing obesity trends

Moderator John G. Kral of SUNY Downstate Medical Center first asked the panelists to comment on how their respective fields should move forward. Lawrence Finer pointed to the "stubborn" problem of unintended pregnancy in the U.S. and blamed the high rate largely on inconsistent use of contraceptives. He argued that organizations should work to increase contraceptive use and advocate long-acting methods, such as IUDs and birth control implants.

Stephen Krawetz talked about the possible use of "precision medicine" to assess genetic damage in sperm. He said data will soon become available demonstrating simple ways to reverse or minimize damage to sperm DNA, perhaps through dietary changes. Nico Rizzo said he would like to see more work to verify and reverse the transgenerational effects of nutrition. Researchers should also look at when such countermeasures could have the greatest impact, such as during early childhood or puberty.

When asked about the association between obesity and unintended pregnancy, Finer pointed to the CDC's Pregnancy Risk Assessment Monitoring System (PRAMS), which collects information about pregnancy and health 6 months after women give birth. The database may include BMI measurements that would help assess the provocative question of whether such a link exists.

Krawetz elaborated on whether developmental changes occur in the sperm during the slow growth period, when Rizzo's research suggests transgenerational effects of nutrition could take place. He explained that the primordial germ cells have started to differentiate in boys aged 10–12 years old. So "it is the million dollar question" whether these cells could be modified at this stage in response to environmental impacts such as poor nutrition, he said. It may be more biologically likely that cells undergo changes later in puberty. One such change could involve the sperm taking up more RNA (which could be active in the zygote) later, while traveling through the epididymis.

Shari Barkin, a conference speaker, asked Nico Rizzo why the effect of paternal grandmothers' nutrition on granddaughters' longevity seemed weaker than the effect of paternal grandfathers' nutrition on grandsons' longevity. Rizzo suggested the difference could be attributable to the Y-line, or sperm line, but emphasized that it is not yet clear how the mechanism could work. He reiterated the need to repeat these studies in other cohorts and in animal models. In some mice studies, grandfathers can influence granddaughters, but Rizzo reminded the audience there could be differences among species.

Krawetz was asked about the heritability of miRNA in sperm given recent studies showing heritability of histone expression patterns. His team's study of 400 men has turned up consistent patterns of RNA molecules in sperm within groups of individuals who share the same fertility potential. At least a couple of miRNAs that are paternally inherited appear to play a role in fecundity. However, because it is difficult to sequence low levels of RNA from single sperm cells, the team analyzes sperm as a pool from each individual, and it is not currently possible to know whether there is consistency among the cells.

Highlights

An upcoming IOM workshop will focus on how early-life exposures modulate obesity risk via epigenetic mechanisms.

Epigenetic modification of metastable epialleles could mediate the effect of maternal diet on offspring traits in humans as in mice.

Rat studies suggest malnourishment, obesity, and BPA exposure during pregnancy could alter the development of appetite neurons and adipocytes in offspring.

Children learn food preferences from flavors they are exposed to in utero and through breast milk and may learn to like fruits and vegetables that are present in the maternal diet.

There are similar levels of macronutrients and calories in breast milk from overweight and normal-weight women.

A workshop on epigenetics

Shari Barkin of Vanderbilt University Medical Center described an upcoming Institute of Medicine (IOM) workshop that will explore how environmental exposures affect a critical window of development between gestation and age 3. It will focus on the external environment (for example, how exposure to adverse childhood conditions can affect adipocyte development and lipid metabolism), the food environment (how diet, both in utero and in early childhood, affects gene expression in different tissues), the developmental environment (for example, how inflammation and epigenetic programming contribute to insulin resistance).

The meeting will also examine epigenetics, aiming to identify how epigenetics mediates the relationship between environmental exposure during the critical early period and obesity later in life. It will also review the science on plastic periods when obesity risk could be mitigated, and look at how to translate epigenetic research into initiatives for obesity prevention and intervention.

Barkin reminded the audience that epigenetic mechanisms, like obesity disorders, are complex and varied. The effects of methylation on gene expression, including expression of obesogenic genes, depends on the tissue type and the location of the methyl group. Information about the IOM workshop is available in the program book from this conference. The workshop materials will also feature webinars, infographics, an IOM Perspective piece, and links to similar forums.

The IOM workshop scheduled for 2015 has three main objectives focused on the role of epigenetics in obesity risk. (Image courtesy of Shari Barkin)

An epigenetic mechanism: metastable epialleles

The effect of environmental exposures on obesity risk, at least in mice, could be modulated through so-called metastable epialleles. As Robert A. Waterland of Baylor College of Medicine explained, these are specific alleles that can be methylated in the fetus in response to maternal nutrition and even before conception, converting cytosines to 5-methylcytosines in the allele. Unlike other types of epigenetic regulation that is tissue-specific, the same methyl pattern occurs in these types of alleles in every tissue in an individual.

The characteristics of metastable epialleles were demonstrated in the agouti viable yellow mouse. When females eat a diet supplemented with methyl donors and cofactors (human-diet equivalents are folate, vitamin B12, and other vitamins) either before or during pregnancy, their offspring may carry more 5-methylcytosines at the agouti locus. Extensive methylation leads to appropriate expression of the agouti protein in the hypothalamus, protecting the offspring from obesity.

Waterland is studying whether this type of epigenetic regulation takes place in humans. By looking for regions of the genome where methylation is random, confirmed by different methylation patterns in alleles from identical twin pairs, and for patterns that appear in several tissues, he has identified 40 genomic regions that may contain metastable epialleles.

In a nutrition study that enrolled women in rural Gambia, he showed that diet during pregnancy was associated with specific methylation patterns in 5 of the 40 genomic regions in children at age 7. Contrary to expectations, children conceived during the dry season, when food is more abundant, had less methylation than those conceived in the rainy season. In addition, the levels of DNA methylation byproducts, such as cytosine and homocytosine, in maternal blood at the time of conception predicted the methylation state of the child's metastable epialleles. "Byproducts may be the best circulating biomarkers of methylation potential," Waterland explained.

Shaping food preference in infants

While epigenetics is an internal mediator of obesity risk, diet and eating habits are classic external mediators. As Julie A. Mennella of Monell Chemical Senses Center discussed, eating habits are established early in life, which is bad news for the many young children who start out eating too much sugar and salt. The pattern is hard to break because mammals have evolved strong preferences for sweet and salty flavors. In one of many experiments revealing this innate preference, newborn babies drank more of a sugar solution when choosing between it and plain water. Children are also drawn to sweets because sugar is comforting and can relieve feelings of pain and stress. The sweet preference is a "beautifully elegant system," Mennella said, because it attracts babies to their mother's milk. But it also makes children vulnerable to unhealthy eating habits because refined sugar and salt are everywhere in today's food market.

The good news, however, is that children's flavor preferences are shaped not just by evolution but also by the foods they are exposed to in the womb, through breast milk, and later when they are weaned to solid foods. Mennella and her colleagues showed that mothers who eat diets rich in healthy foods during pregnancy and lactation can get children off to a good start. Flavors are transmitted from the maternal diet to amniotic fluid and breast milk, and experience with such flavors leads to greater acceptance of those foods at weaning. In contrast, infants fed formula learn to prefer its unique flavor profile and may have more difficulty accepting new flavors. Nonetheless, all infants can learn through repeated exposure and dietary variety. Introducing children repeatedly to fruits and vegetables within and between meals may help them be more accepting of these foods, although flavor preference is difficult to enhance beyond toddlerhood.

Mennella pointed to the special responsibility that companies making food products for children have in shaping eating behavior. Nonnutritive sweeteners are now in many products, such as cereals, and "children are learning from an early age that foods that are not sweet are meant to taste sweet," she said. There is a paucity of research on how this will impact children's taste choices.

Intrauterine exposures in rats

Mina Desai and Michael G. Ross of the University of California, Los Angeles, discussed three rat models that support the importance of the intrauterine environment in childhood obesity. In the first, female rats were fed a restricted diet during the second half of pregnancy to look at the long-term effects of low birth weight. In the second, females received a high-fat diet before and during pregnancy to capture the effects of maternal obesity. Newborns from underfed mothers received normal nursing but overfed mothers nursed their own pups. Both offspring groups were weaned onto normal diets. Although newborns from underfed mothers started out underweight, by several months after birth they became fat, similar to the offspring from overfed females. This effect seems to replicate the association in humans between low birth weight and higher risk of metabolic syndrome. In the third model, females were given drinking water containing bisphenol A (BPA), a known endocrine disruptor present in food packaging that has been shown to concentrate in amniotic fluid. By 6 months old the male, but not female, offspring were heavier than control animals.

Ross explained the observations that Desai and he have made from these models. Pups from under- or overfed mothers eat more and have different numbers and types of neurons in the arcuate nucleus region of the brain, which controls appetite. The experiments so far suggest that the offspring of undernourished rats have fewer neurons in this region, but a greater proportion of the neurons are neuropeptide Y–expressing (NPY) neurons that drive appetite and there are fewer pro-opiomelanocortin–expressing (POMC) neurons that drive satiety. Pups from females fed BPA appear to have more neurons overall, but it is not clear yet how many differentiate into NPY or POMC cells.

Desai talked about the distribution and characteristics of fat cells, or adipocytes, in these rat models. The offspring of food-restricted mothers have more pre-adipocytes (adipocyte stem cells) and bigger adipocytes (mature cells that are able to store more fat). These pups, along with pups born to BPA-exposed mothers, also have more differentiated adipocytes, and these cells appear to be more sensitive to storing lipid fats in response to insulin. Thus, both nutrition and BPA have the ability to modulate stem cells, impacting proliferation and differentiation.

Is all breast milk the same?

Nancy F. Krebs of the University of Colorado School of Medicine described the importance of infant diet up to 6 months of age. Excessive weight gain during this time is linked to greater risk of overweight and higher blood pressure during childhood. And while exclusive breast milk is the recommended diet for babies in this period, and may also help protect against later obesity, Krebs and other pediatricians wondered, "'Is all milk the same?'"

Research in mice suggests that it is not. A study found that pups born to lean females and breastfed by obese females grew to be heavier and consumed more calories than pups born and breastfed by lean females. However, preliminary findings by Krebs and her colleagues suggest that breast milk from obese and normal-weight women is similar in calorie density and levels of macronutrients and other components. Breast milk from overweight women had higher levels of insulin and leptin, an appetite-suppressing hormone, in agreement with other studies. But these differences were not associated with differences in infants' early growth.

"This suggests that it is perfectly safe to be breastfeeding, and in fact it may be really important to minimize the risk of maternal obesity," Krebs said. However, in some cases breastfeeding could increase weight gain in infants; some women, regardless of BMI, make breast milk so rich it is like cream. Overall, however, the risk of rapid infant weight gain and later obesity is probably greater for formula-fed babies.

Preliminary data by Krebs suggest that breast milk calorie density is related to babies' weight gain but not to maternal BMI. (Image courtesy of Nancy F. Krebs)

Highlights

Satiety responsiveness is linked to meal portion and weight in young children.

The low rate of physical activity among children and teens in the U.S. is affected by environmental conditions such as weather and safety.

A hormone called irisin may recapitulate the beneficial effects of exercise on brain function.

Novo Nordisk is testing the effectiveness of a health education program for young couples that aims to instill healthy habits before pregnancy.

The role of appetite in childhood obesity

Jane Wardle of University College London studies whether genetic and environmental risks for obesity act through appetite. To study appetite, she and her colleagues developed the Child and Baby Eating Behaviour Questionnaires (CEBQ, BEBQ), which measure food responsiveness (the desire to eat when seeing or smelling food) and satiety responsiveness (the desire to stop eating in response to fullness). They found that as weight increased in children aged 8–12 years old, food responsiveness increased and satiety responsiveness decreased, in agreement with studies dating back to the 1960s.

The obesity epidemic is driven by genetics and environment, and this model posits that both factors affect appetite. (Image courtesy of Jane Wardle)

To look at the role of genetics in obesity and appetite, Wardle is investigating two cohorts of monozygotic and dizygotic twins: the Twins Early Development Study (TEDS), which she started following when the twin pairs were 5 years old; and the GEMINI twin study, which she has followed since the twins were 3 months old. Studies of both cohorts suggest appetite is hereditary. Furthermore, single nucleotide polymorphisms (SNPs) that have been positively associated with obesity are also negatively associated with satiety responsiveness. In addition, satiety responsiveness is linked to meal size, which in turn has been shown to be a predictor of weight gain in young children.

Wardle made the case that satiety responsiveness should receive more research attention. Just as nutritionist Jean Mayer argued in the 1950s, food intake is controlled today not just by when we eat but also by how much we eat, which is controlled in turn by satiety. Understanding satiety response "provides us with opportunities for novel treatment approaches and potentially advice in terms of prevention," Wardle said.

GEMINI and TEDS twin cohort studies suggest that appetite is about 70% heritable. (Image courtesy of Jane Wardle)

Physical activity and brain function

Christiane Wrann of Dana-Farber Cancer Institute talked about the potential for exercise to reset brain function. Intervention studies have found that when older adults regularly perform strenuous exercise they can recover brain connectivity typical of a much younger adult. Studies in mice have shown that a protein called brain-derived neurotrophic factor (BDNF) is important for the mental perks of exercise, possibly because it stimulates neuronal cell growth and differentiation. Unfortunately, however, clinical trials of BDNF injection for amyotrophic lateral sclerosis showed little benefit, probably because of inadequate delivery of the drug to the brain. Wrann began to search for other molecules that could stimulate BDNF or otherwise mediate the mental and possibly metabolic benefits of exercise.

FNDC5, a transmembrane protein made by muscle cells in response to endurance exercise, had recently been identified in her lab. The protein is cleaved into a form called irisin, a hormone that converts white fat to brown fat. Wrann's experiments indicate that FNDC5 could also play a role in the brain, where it has been detected and found to turn on a program of genes, including the BDNF gene, that are associated with neurogenesis. Because it circulates in the blood, irisin could potentially be used as a therapeutic, and Wrann is currently testing how injecting this protein affects memory in mice.

Early diabetes prevention

Susanne Stormer described work at Novo Nordisk, a Copenhagen-based company working to combat the diabetes epidemic. One program aims to improve diabetes care by providing insulin treatment and patient education. Another, in partnership with the Malaysian government and conducted through the company-owned Steno Diabetes Center, is testing whether providing health information to young married couples before pregnancy can improve health outcomes. Stormer noted the project is one of the first public–private health partnerships in the world. As she explained, "Malaysia is painfully experiencing ... the epidemic rise in diabetes that comes with economic development."

The couples in the study have poor diets: "They eat out and have adopted some Western habits and lifestyles that are not conducive to having healthy children," she said. The researchers are studying whether encouraging good eating and exercise habits can reduce the rates of gestational diabetes, and in turn diabetes among children. They hope to have interim results within 2 years.

Stormer also briefly discussed the Cities Changing Diabetes initiative, aimed at understanding the environmental factors contributing to urban diabetes and developing partnerships with mayors, city leaders, local communities, businesses, and health care professionals to reduce diabetes prevalence in several cities around the world.

Physical activity and obesity

In his second talk at the conference, Nico S. Rizzo presented dismal figures on physical fitness in children and adolescents. In the U.S., about 30% of 6- to 19-year-olds are overweight and about 15% are obese. About 77% of 9- to 13-year-olds engage in free (not organized) physical activity. However, only 11% of high school girls and 24% of high school boys are physically active.

Rizzo presented two studies in children and adolescents in Sweden. He looked at how physical activity, body fat, and other health measures impact one another. Although only vigorous exercise resulted in reduced body fat, milder exercise improved cardiovascular and cardiorespiratory fitness. These cardio benefits were seen in children as young as 9 years old, which Rizzo found "remarkable." In measures of cardiorespiratory fitness, girls benefited more than boys from physical activity at both 9 and 15 years old.

Rizzo pointed to environmental factors that can influence physical activity, such as school and home environments, weather conditions, and safety. Not surprisingly, physical activity was highest in the warmer spring months. His team is also looking at the role of geography in obesity risk by examining the contribution of county of residence, particularly the county's obesity prevalence, along with lifestyle factors. He mentioned that even people who maintain a healthy diet and do regular physical activity experience a higher obesity risk if they live in a county where the prevalence of obesity is high.

How can we design urban environments to promote walking, food diversity, and safety?

Can we replenish our gut microbiome with the bacteria lost during urbanization and reduce rates of autoimmune disorders?

What is the function of the various classes of RNA that sperm cells deliver to oocytes?

Do metastable epialleles function in the same way in humans as in mice to mediate the effect of maternal diet during pregnancy on obesity risk in offspring?

Which intrauterine exposures are important for determining obesity risk, what are their mechanisms, and when are the optimal times to intervene?