Description of Research Expertise:
The principal goal of our research program is to elucidate the underlying molecular mechanisms that link fetal growth retardation to the later development of obesity and type 2 diabetes in adulthood. We currently have 3 major projects and several smaller projects. The first project focuses on the relationship between oxidative stress and ß-cell dysfunction and insulin resistance. We have developed a model of fetal growth retardation in the rodent (mice and rats) which leads to the later development of diabetes and obesity in adult animals. We have established that fetal growth retardation induces progressive mitochondrial dysfunction, oxidative stress, mtDNA mutations, and electron transport defects. These defects cause abnormal ß-cell function and development, and hepatic and muscle insulin resistance. Oxidative stress decreases transcription of key genes related to ß-cell development, induces modifications of proteins of the Krebs cycle in the liver, and muscle. Pdx-1 is a critical transcription factor that regulates ß-cell function and development. Transcription of this gene is permanently down-regulated in ß-cells of IUGR rats leading to a gradual reduction in ß-cell function and ß-cell replication. We have determined that oxidative stress induced by uteroplacental insufficiency in IUGR fetal pancreas induces aberrant methylation and chromatin remodeling at the Pdx-1 promoter, which in turn induces transcription silencing. The focus of the second project is to determine whether the effects of an aberrant intrauterine milieu can be reversed after birth, we have designed a number of therapeutic modalities including diet modifications and antioxidant treatment. In collaboration with Dr. Doris Stoffers, we have successfully prevented the development of diabetes in IUGR rats with several of these treatments. Administration of a pancreatic ß-cell trophic factor, Exendin-4, during the neonatal period dramatically prevents the development of diabetes in our model. Neonatal Exendin-4 treatment prevents the progressive reduction in ß-cell mass that is observed in IUGR rats over time. Expression of Pdx-1 is restored to normal levels, and islet ß-cell proliferation rates are normalized by the neonatal Exendin-4 treatment. Of major clinical significance is our finding that Exendin-4 treatment in the newborn period prevents the onset of obesity in IUGR rats. This surprising finding has stimulated a new direction for this project and we are currently determining the mechanisms by which Exendin-4 treatment reverses epigenetic modifications such as DNA methylation and histone modifications of key genes related to ß-cell development. The third project is focused on the effects of obesity during pregnancy and the long-term outcome in the offspring. The specific aims of this project are to determine the window of susceptibility of the developing organism to the effects of obesity during gestation, determining whether regulation of the adipogenic pathway is altered in offspring, and defining the molecular mechanisms responsible for enhanced adipogenesis observed in offspring of obese mothers.
1. Cell culture and animal models to study fetal programming (the effect of an abnormal in-utero environment- IUGR, obesity, diabetes-upon fetal growth and development and the later development of obesity and diabetes).
2. Epigenetic regulation of gene expression (DNA methylation and histone acetylation and methylation) using bisulfite sequencing and ChIP assays
3. Measures of Mitochondrial function-oxidative phosphorylation and electron transport chain activity.
Stoffers DA, Desai BM, DeLeon DD: Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat Diabetes 52 (3): 734-740,2003.
Selak MA, Storey BT, Peterside IE: Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats Am J Physiol Endocrinol Metab 285 (1): E130-E137,2003.
Chennathukuzhi V, Stein JM, Abel T, Donlon S, Yang S, Miller JP, Allman DM, Simmons RA: Mice deficient for testis-brain RNA-binding protein exhibit a coordinate loss of TRAX, reduced fertility, altered gene expression in the brain, and behavioral changes Mol Cell Biol 23 (18): 6419-6434,2003.
Peterside IE, Selak MA: Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats Am J Physiol 285 (6): E1258-1264,2003.
Pallotto EK, Macones GA: Small for gestational age infants at risk for prolonged hypoglycemia Epidemiology : 2003.
Pallotto EK, Woelnerhanssen B, Macones G: Hypoglycemia in small for gestational age infants: How extensive is the problem and what are the risks? Pediatr Res 53 : 499A,2003.
Simmons RA: Intrauterine growth retardation increases oxidative stress and induces mitochondrial DNA deletions in rat ß-cells Pediatr Res 53 : 804A,2003.
Vuguin P, Raab B, Xiaohui-Ma, Liu B, Barzilai N, Stoffers DA: Exendin-4 decreases body weight and improves insulin action in intrauterine growth retarded rats. Pediatr Res 53 : 877A,2003.
Simmons RA, Crutchlow M, Desai BM: Reduced islet vascularity in intrauterine growth retarded rats Endocrinology : PI-295,2003.
Simmons: Cell glucose transport handling during fetal and neonatal development Fetal and Neonatal Physiol : 2003.