Development, epigenetics, and the "diabesity" epidemic.

Abstracts

The Potential Impact of Epigenetics on Obesity and Diabetes
Robert A. Waterland, PhD
Baylor College of Medicine

An obesity epidemic is underway in the US and many other developed countries, and is associated with an increasing prevalence of type 2 diabetes, dyslipidemia, and hypertension. It has long been presumed that genetic variation alone explains individual differences in obesity susceptibility. A complementary explanation is that individual susceptibility to obesity is determined not only by genes but also by environmental influences during development. Early environment can affect the developmental establishment of epigenetic gene regulation, providing a potential biologic mechanism for such 'metabolic imprinting' of obesity susceptibility. Epigenetics is the study of mitotically heritable alterations in gene expression potential that are not caused by changes in DNA sequence. Just as genetic variation affects individual susceptibility to obesity, so too could individual epigenetic variation. Indeed, extensive data demonstrate that epigenetic dysregulation can cause obesity. Our data in an inbred mouse model indicate that maternal obesity has an obesogenic effect on her offspring. Dietary methyl donor supplementation prevents this effect, suggesting a role for epigenetic mechanisms including DNA methylation. I will describe ongoing studies using DNA methylation microarrays to explore the hypothesis that interindividual variation in hypothalamic epigenotype is established during development and persists to affects adult body weight regulation.

Establishing Household Practices to Reduce the Intergenerational Transmission of Obesity
Robert C. Whitaker, MD, MPH
Temple University

Protection from and risk of obesity is transmitted across generations through an interaction between genes and the prenatal and postnatal environments. To break the intergenerational transmission of obesity, when during the life cycle and with what approaches would it be most helpful to intervene? The best time to intervene is the period from before children are conceived until they reach school age. Families are the social unit with greatest potential influence during this part of the life cycle because parents can establish household practices affecting children's environments. Helping parents establish these household practices requires a better understanding of 1) where healthy weight fits among all the aspirations that parents have for their children's physical, social, emotional and cognitive development, and 2) how extended family and the neighborhood can either support or undermine household practices. There are several areas in which household practices might optimize children's development while also preventing obesity. These include having regular family meals, encouraging unstructured outdoor play, and establishing sleep routines. If parents achieved a healthy weight before becoming pregnant and lengthened the interval between pregnancies, these household practices might also improve family wellbeing and prevent obesity.

Molecular Genetics of Susceptibility to Obesity and Type 2 Diabetes
Rudolph L. Leibel, MD
Columbia University

Both obesity and T2D are complex traits with clear evidence of strong genetic predisposition. Such disposition is influenced by development, environment and genetic context ("background"). In most instances, single genes (or perhaps even a few genes) do not appear capable of accounting for a substantial fraction of risk, though single gene (or pathway) targets may provide effective therapeutics. Because the underlying physiologies are complex and overdetermined, the unfolding genetic complexities should not be surprising. It has recently become possible to "score" 106 or more single nucleotide polymorphisms (SNPs) across the 3x109 bp human genome at reasonable cost. Very large (5x104 or more) collections of well phenotyped individuals, scored for such SNPs, will be needed to identify relevant genes with modest individual impact and to begin to examine their interactions. These approaches will revolutionize the way that genetic analysis of complex human medical phenotypes is done. Many of the genes identified in this way are likely – by virtue of the essentially hypothesis – free nature of such statistical approaches – to be previously unknown and/or of unknown function. Strategies for vetting their molecular physiologies will be critical to the ability to apply these insights in medicine.

Maternal In-Utero Environment: Short and Long Term Effects on the Offspring
Patrick M. Catalano, MD
Case Western Reserve University
Obesity's increasing prevalence has reached epidemic proportions not only in the United States but in developing areas of the world. The maternal, fetal, perinatal and neonatal complications of obesity in pregnancy have far reaching implications for both the mother and the offspring. For the mother, there is the increased risk of the metabolic syndrome. In the fetus, there is an increased risk of perinatal morbidity including such problems as fetal adiposity and congenital anomalies. Although the issue of fetal origins of adult disease and long term risk to the offspring were initally focused on the growth restricted fetus, there has been mounting evidence that there is a significant increase in long term morbidity for the macrosomic offspring of the women with both gestational diabetes and obesity. We review the evidence of both short and long term effects of maternal obesity on the intrauterine environment as it relates to fetal growth, neonatal body composition and adolescent metabolic dysfunction.

Learning objectives: to understand the factors relating to fetal growth and adiposity; knowledge of fetal growth and body composition during the first year of life; and maternal factors related to adolescent obesity and metabolic dysfunction.

Preventing Maternal-Fetal Overnutrition
John G. Kral, MD, PhD
SUNY Downstate Medical Center

The increasing prevalence of maternal obesity has caused increases in gestational complications, maternal mortality and offspring overnutrition. Unplanned pregnancies occur in >80% of poor women, impeding pre-conception weight-loss treatment. Rapid gestational weight gain is an independent risk factor for adverse pregnancy outcomes and offspring overnutrition, type 2 diabetes, fatty liver disease and hypertension leading to poor adult health. Guidelines for maximum gestational weight gain are lacking. Existing guidelines are outdated and inadequate; obese women are commonly instructed to exceed Institute of Medicine standards for minimal weight gain. The very few prospective studies of gestational weight gain restriction do not specifically address pregnancy complications or offspring outcomes. Surgical treatment of severe obesity, achieving substantial voluntary weight loss in pre-menopausal women, has been performed for 50 years, increasing dramatically over the last 20 years in step with the prevalence of obesity and improved perioperative safety. Comparisons of pregnancies before and after maternal obesity surgery provide information for determining optimal gestational weight changes in obese mothers. This presentation will review the literature on pregnancy outcomes for mother, fetus and child followed into adolescence after maternal antiobesity surgery, while discussing mechanisms of surgery and requirements for management, providing evidence for ethical euphenics related to primary prevention of prevalent chronic metabolic diseases.

Breast Feeding and Offspring Obesity
Andreas Plagemann, MD
University of Medicine Berlin

Breast feeding is the best way to nurture healthy newborns of healthy mothers. A number of studies have shown that breast feeding may protect against the later development of obesity and related metabolic diseases. Using data from an own meta-analysis as well as studies by other groups, the current state of evidence regarding this topic is reviewed. Breast feeding, in general, is shown to be associated later in childrens life with a decreased risk of overweight, decreased blood cholesterol, blood pressure, and a reduced risk of developing type 2 diabetes. Data of our Kaulsdorf Cohort Study (KCS) show, however, that these effects might be even reversed when the mother suffers from diabetes, which can alter the composition of breast milk. In particular, exposure to breast milk from diabetic mothers during the first days of life (first week; early neonatal period) seems to increase rather than decrease risk of overweight and, consecutively, impaired glucose tolerance in childhood. In rats, this is accompanied with malprogramming of hypothalamic circuits regulating food intake, body weight and metabolism. Taken together, current findings show clearly that breast feeding is effective in lowering the risk of developing key features of the Metabolic Syndrome in later life, and should therefore be promoted. With increasing prevalence of overweight and diabetes in women, however, more research is urgently needed to clarify whether breast feeding might even have negative consequences for risk of overweight and diabetogenic disturbances when the mother suffers from diabetes. From a more general perspective, breast feeding and its long-term consequences are an important paradigm for 'perinatal programming' of health and disease.

Young Children's Eating Behavior: Individual Differences and Their Implications for Weight Development
Tanja V.E. Kral, PhD
University of Pennsylvania

Experimental studies have shown that infants and young children possess an innate ability to regulate short-term energy intake. As children grow older, however, this regulatory ability appears to weaken. Environmental factors, such as overly restrictive feeding practices (Birch et al., 2003) or exposure to large portions of energy-dense foods (Fisher et al., 2007), have been identified as potential culprits behind an increased energy intake in children.

While these environmental factors seem to affect children with a range of individual characteristics (e.g., body weight, age, sex), there do exist considerable interindividual differences in how responsive children are to these external cues. These individual differences in eating behaviors and the ability to regulate short-term energy intake presumably are influenced by children's differential familial predisposition to obesity. Factors pertaining to the home family environment (e.g., parental feeding practices) have been systematically studied in the past; however, only limited data are available on the heritability of eating traits.

The purpose of this talk is to review selected eating behavior phenotypes in children at various stages of their lives and to elucidate how individual differences in these traits may predispose children to increased energy intake and weight gain.

For example, eating in the absence of hunger (EAH) has been identified as a behavioral eating trait which refers to children's susceptibility to eating in response to the presence of palatable foods in the absence of hunger. There is evidence for both genetic and nongenetic familial environmental influences on EAH. Specifically, the trait has been shown to be highly heritable (h2 = 0.51) (Fisher et al., 2007). At the same time, children who experience greater restriction in their access to palatable foods in their home tend to exhibit more pronounced EAH (Birch et al., 2003). Thus, parental feeding practices may interact with children's genetic predisposition to obesity to promote greater EAH. Given that EAH is a relatively stable eating phenotype which shares behavioral characteristics with disinhibited eating in adults, this eating phenotype may be considered an early behavioral marker or risk factor for obesity onset.

The talk will conclude with a discussion about possible implications of the current state of knowledge in the area of pediatric ingestive behavior for the prevention and treatment of childhood obesity.

Gene x Environmental Interactions' Effects on Offspring Obesity
Barry E. Levin, MD
UMDNJ

Maternal undernutrition, obesity and diabetes during the perinatal period can all produce obesity in human offspring. Animal models allow assessment of the independent consequences of altering the pre- vs. postnatal environments on a variety of metabolic, physiologic and neuroendocrine functions which lead to offspring obesity and diabetes. During gestation, maternal malnutrition, obesity, type 1 and type 2 diabetes and psychological and pharmacological stressors can all promote offspring obesity. Postnatal nutrition and maternal-offspring interactions can ameliorate or exacerbate the effects of an adverse prenatal environment. An individual's genetic background is also important determinant of outcome when the perinatal environment is perturbed. Perinatal maternal obesity in rats with an obesity-prone genotype accentuates the development of offspring obesity. While epigenetic changes in gene expression can occur, many perinatal perturbations cause disordered development of the central neural pathways which regulate food intake, energy expenditure and storage in ways that promote offspring obesity. Both leptin and insulin have strong neurotrophic properties so that either an excess or a reduction of either during the perinatal period can produce adverse neural development. Because perinatal manipulations can permanently and adversely alter the systems which regulate energy homeostasis, it behooves us to gain a better understanding of the factors which promote the development of offspring obesity as a means of stemming the tide of the emerging world wide obesity epidemic.

Perinatal Programming of Neural Circuits Regulating Energy Homeostasis
Sebastien G. Bouret, PhD
University of Southern California

Brain development is influenced by a variety of environmental signals and circulating hormones exert widespread actions on formation of neural circuitry. Evidence accumulated primarily in mice specifically indicates that the adipocyte-derived hormone leptin is a key neurodevelopmental signal affecting the architecture of hypothalamic circuits mediating food intake and adiposity. Its acts directly on neurons in the hypothalamus to promote axon outgrowth during a discrete developmental critical period that coincides with the naturally occurring surge in leptin.

Accumulative evidence also suggests that alterations in perinatal nutrition (such as caloric restriction or overfeeding) during critical periods of pre- and postnatal development can predispose an individual toward obesity and associated diseases such as type 2 diabetes. To further study the neurodevelopmental changes associated with this metabolic imprinting, we developed a divergent litter size mouse model of perinatal overnutrition and undernutrition. Nutritional manipulation during lactation was associated with changes in the amplitude of the leptin surge during postnatal life and overall growth as revealed by a significant decrease and increase in preweaning body weight curve of neonatally underfed and overfed animals, respectively. In addition, both neonatally under- and overnourished animals develop insulin intolerance. Consistent with our findings in leptin-deficient mice, development of hypothalamic neural circuits appear abnormal in both neonatally underfed and overfed neonates.

Collectively, these data indicate that perinatal hormones (particularly leptin) represent key signals that program development of neural circuits involved in energy homeostasis. These data also show that early nutrition influences postnatal leptin secretion and suggest that it has long-term consequences on brain development and on metabolism.

Primate Models of Maternal-Fetal Interactions Predisposing to the Development of Obesity and Diabetes
Peter W. Nathanielsz, MD, PhD, ScD
University of Texas Health Science Center

The concept of developmental programming is now well accepted on the basis of human epidemiologic and animal studies. Most of the animal studies have been conducted in rodents and sheep. Several important nutritional differences exist between sheep and rats and primates. Adult sheep are ruminants and hence maternal carbohydrate and fatty acid metabolism differs from primates. Rats are polytocous species. A 250 gram female rat may have a litter of 16 pups each weighing 6 grams. The biomass that she is nurturing equals an additional 40% of her own body weight in fetuses, equivalent to a 160 pound woman delivering a 64 pound baby. Both ruminants and rodents have made valuable contributions to our understanding of developmental programming and observations made in these species can be used to determine similarities with, and differences from primates. Primate models do however also present experimental challenges in the control of nutrition, maintenance of maternal exercise, and dominance structures and stress. One of the major practical strengths is the availability of human reagents that generally cross react in nonhuman primate tissues. This presentation will deal with approaches to study key organs – liver, skeletal muscle and adipose tissue, and cell signaling systems – growth and insulin signaling, in the fetal nonhuman primate.

An Epigenetic Metabolic Syndrome in a Nonhuman Primate Model of Early Life Adversity: Neurotrophic Correlates
Jeremy D. Coplan, MD
SUNY Downstate Medical Center

Early environmental adversity may produce persistent epigenetic alterations that set the stage for insulin resistance, metabolic obesity and Type II diabetes. Overactivation of the corticotrophin releasing factor/ HPA axis system and reduction in neurotrophic gene expression may set the stage for disease onset. A nonhuman primate model of early adversity is achieved through exposure of infants to compromised maternal rearing induced by unpredictable or variable foraging demand (VFD). VFD-reared subjects exhibit accelerated onset of visceral adiposity and insulin resistance, which is predicted by the magnitude of maternal HPA axis disturbance. The degree of asymmetry of hippocampal volume and spectroscopic metabolites (right > left) predicts relative elevations in body mass index and plasma cholesterol. Relative elevations of the insulin/glucose ratio inversely predict reductions in white matter integrity of the internal capsule using diffusion tension imaging. In the dentate gyrus, rates of neurogenesis and expression of the anti-apoptotic gene factor BCL2, are inversely predicted by blood sugar and body weight. These data are supportive of the hypothesis that long-term epigenetic compromise of neurotrophic influences following early life adversity is associated with metabolic syndrome in the periphery and compromised neuroplasticity within hippocampus and white matter tracts of the CNS