The long-term goal of this project is to understand more clearly the biological basis for obesity and its co- morbid conditions, hypertension and Type 2 diabetes mellitus. Since increasing evidence links prevalence rates of obesity and related disorders in adults with indices of body growth during fetal and neonatal life, events in early life appear to influence the likelihood that an individual will acquire these conditions in later years. This application is founded on the premise that the sympathetic nervous system (SNS) is a key intermediary in this process, responding to environmental factors and altering development of the innervated tissues. One predisposing factor which may be especially important for SNS development and obesity is the quantity and quality of maternal food intake. Based upon similar changes in sympathetic innervation in several different animal models of developmentally-induced obesity, this application focuses specifically on nutrient-induced alterations in SNS development in pancreas and retroperitoneal fat. Maternal exposure to diets enriched in refined carbohydrates (sucrose and starch) increases SNS innervation in these two tissues, while intake of fructose or animal fat decreases it.
The aims of this proposal are to characterize more fully the impact of maternal and neonatal nutrition on sympathetic and parasympathetic development and their consequences for structure and function of pancreatic islets and retroperitoneal fat. Studies will examine effects of pharmacological interventions on the developing SNS, employing chemical sympathectomy in circumstances of increased SNS and neuroprotective agents in settings of decreased SNS, and assessing their impact on tissue mass and on insulin secretion and action. Finally, since the SNS participates in adaptive responses to pregnancy, studies will examine the consequences of altered SNS development in female animals on sympathetic responses to pregnancy and their implications for glucose homeostasis. The route from fetal and neonatal life to subsequent obesity may follow several paths;one involves impaired and another enhanced early growth. Corresponding changes in SNS development appear to accompany these differences in growth in experimental animals. Identifying connections among growth, SNS development and obesity offers a potential means for identifying obesity-prone individuals early in life with the ultimate objective of intervening in an effective and appropriate manner.
| Oh, Eunjin; Miller, Richard A; Thurmond, Debbie C (2015) Syntaxin 4 Overexpression Ameliorates Effects of Aging and High-Fat Diet on Glucose Control and Extends Lifespan. Cell Metab 22:499-507 |
