Developmental Origins of Disease

Mammalian fetal development is dependent on the constant maternal supply of nutrients. Any aberrations in maternal metabolism, due to inappropriate nutrient intake or underlying metabolic disease, directly impact maternal/fetal flow of fuel and energy building blocks. Potential consequences of an unfavorable intrauterine environment include not only immediate effects on the fetus, but also long-lasting effects, which manifest during adulthood in these offspring. The latter phenomenon has been termed “fetal origins of adult disease,” or intrauterine programming of disease, and may be intimately related to disproportionate fetal growth during periods of altered maternal nutrition. These transgenerational events are related to infant birth weight and are U-shaped, meaning that they are associated with both fetal macrosomia, as in the case of maternal insulin resistance, and with fetal growth restriction, as in the case of severe maternal diabetes or malnutrition. The observation that offspring of type 1 (insulin-dependent) diabetic mothers with poor metabolic control have shorter femur lengths for thigh circumference after 30 weeks gestation suggests that fetuses of diabetics exhibit altered growth at the level of cell differentiation and very early mechanisms controlling body composition. This could contribute to manifestations of metabolic disease in the adult life of the offspring. Maternal obesity and diabetes in pregnancy and birth weight have also been linked to aspects of metabolic syndrome in childhood and adulthood and the attendant increased risk for atherosclerosis.

Jean E. Schaffer, MD, is the Virginia Minnich Professor of Medicine and director of the Diabetes Research and Training Center at Washington University School of Medicine. Her research interests include diabetes, lipotoxicity and heart disease. The worldwide epidemic of diabetes and obesity presents a formidable challenge because of the serious cardiovascular complications of these disorders. Both diabetes and obesity are known risk factors for coronary artery disease, and diabetics often have a more clinically aggressive form of the disease than their non-diabetic counterparts. Cardiomyopathy, independent of coronary atherosclerosis, is a frequent complication that contributes significantly to increased morbidity and mortality among affected individuals. Evidence is emerging that in diabetic and obese individuals, dyslipidemia leads to fatty acid accumulation in non-adipose tissues such as the myocardium or endothelium, which results in cellular dysfunction and cell death and contributes to organ dysfunction, a process known as lipotoxicity. Similarly, dyslipidemia may contribute to other end organ complications and play a key role in transmitting increased cardiovascular risk to offspring. Not only are the risks for cardiovascular disease apparent in diabetic and obese individuals, but also epidemiological studies indicate that this risk is transmitted transgenerationally from obese and diabetic mothers to their offspring, in part through epigenetic influences of the intrauterine environment.

The goals of studies in the Schaffer lab are to characterize the fundamental cellular mechanisms of lipotoxicity and to understand how these processes contribute to organ dysfunction in rodent models of metabolic disease. Her work involves genetic screens in cultured cells to identify key molecular players in the lipotoxic response, as well as experiments to elucidate the contributions of these genes and their products in genetic mouse models of obesity and diabetes and in transgenic mice with lipotoxic cardiomyopathy. In addition, Schaffer is working with Kelle H. Moley, MD, to develop a murine model in which to study the role of the intrauterine environment as a determinant of metabolic syndrome, obesity and diabetes in adult offspring. The goal of these studies is to understand mechanisms of metabolic imprinting.

In an effort to translate our basic studies to understanding of human disease, Schaffer is also collaborating with clinical investigators to define the correlates between altered systemic lipid metabolism and early diabetic cardiomyopathy in asymptomatic human subjects with type 2 diabetes. Her long-term goal is to develop novel lipid biomarkers and noninvasive methods for diagnosing the earliest structural and functional abnormalities in diabetic cardiomyopathy and for guiding therapy that may be applied to population-based practice.

Kelle H. Moley, MD, is the James P. Crane Professor of Obstetrics and Gynecology and professor of Cell Biology and Physiology. Moley’s laboratory reported a detrimental in vitro effect of high insulin and IGF-1 levels, characteristic of an insulin-resistant state. The Moley lab exposed preimplantation embryos are insulin resistant and have abnormal AMPK activity. Fetuses resulting from transfer of these embryos experience subsequent fetal growth abnormalities. The lab has also demonstrated that mice fed a diet high in saturated fatty acids for 16 weeks produce fetuses that are smaller at embryonic day 14.5 and demonstrate some of the same abnormalities as those exposed to high IGF-1 in vitro. In addition, the placentae from these high-fat diet (HFD) mice have increased Igf2r mRNA. Moreover, preliminary data reveal that these HFD mice deliver smaller pups that quickly catch up in growth and develop early signs of metabolic syndrome. This suggests a direct relationship between maternal nutritional state and feto-placental growth at the earliest stages of development. Also, these results suggest that perhaps the maintenance of imprinted genes may be modulated by nutrition at this critical time in development. The manifestations of these earliest embryonic effects on the phenotype of the offspring have not been investigated previously, but may account in part for developmental programming of adult disease. Her current hypothesis is that the metabolic milieu of maternal obesity and insulin resistance during pregnancy adversely affects development and contributes to the risk of obesity, diabetes and cardiovascular disease in offspring. In addition, Moley speculates that the vulnerable period in development at which the metabolic milieu plays a role in long-term outcome of the fetus is during the blastocyst stage of the preimplantation period. The rationale behind this work is that identifying the timing and mechanisms of programming could allow dietary or pharmacologic measures to be started earlier and maintained during the critical period to prevent serious sequelae in offspring and perhaps slow the epidemic of obesity.

Clay F. Semenkovich, MD, is chief of the Division of Endocrinology, Metabolism and Lipid Research, program director of the Endocrinology, Diabetes and Metabolism fellowship program, the Herbert S. Gasser Professor of Medicine and professor of cell biology and physiology at Washington University. The Semenkovich lab is interested in lipid metabolism and how it promotes atherosclerosis in the setting of obesity, insulin resistance and diabetes. Fats are partitioned to tissues in highly regulated ways. Excess lipids directed to adipose tissue are stored and lead to obesity, a disorder associated with diabetes, insulin resistance and heart disease. His lab engineered mice with ectopic and inducible expression of uncoupling protein-1 (UCP-1) in specific tissues. UCP-1 is an inner mitochondrial anion transporter that uncouples respiration and oxidative phosphorylation. These animals are being used to study the role of metabolism in age-related diseases such as atherosclerosis and hypertension. His research is also interested in the fetal and developmental origins of cardiovascular disease and metabolic syndrome.

SUMMARY
The worldwide epidemic of obesity and diabetes presents a formidable challenge because of the serious complications of these disorders. Maternal obesity and diabetes are associated with infant growth abnormalities, both small-for-gestational age (SGA) and large-for-gestational age (LGA), and subsequent increased risk of obesity, diabetes and metabolic syndrome in the offspring. The mechanisms underlying this increased risk in offspring are not well understood, but likely involve both genetic and environmental effects. Both early pre-implantation and later post-implantation insults have been implicated. These three investigators are interested in the hypothesis that the metabolic milieu during pregnancy influences the risk for adult obesity, diabetes and cardiovascular disease in offspring, independent of genetic influences. All three researchers are employing genetic and diet-induced mouse models of obesity and diabetes to characterize the timing and mechanisms underlying these phenomena. In addition, they are writing a challenge grant to look at the developmental origins of these diseases using maternal models of obesity and metabolic disorders. WRHR junior faculty members would have access to all three of these investigators, the Diabetes Research Training Center and the Clinical Nutrition Research Units at the School of Medicine to answer these questions.