Obesity is an important clinical problem that is associated with complications such as diabetes and heart disease. The Zucker obese rats have been used extensively in obesity research. Obesity in Zucker rats is an autosomal recessive trait caused by the mutated gene """"""""fa"""""""". The phenotype shows several behavioral, metabolic and endocrine abnormalities such as hyperactivity, hyperphagia, hyperlipidemia, hyperinsulinemia, increased fat deposition and fatty liver. Hyperplastic changes in the obese Zucker adrenal cortex, hypersecretion of adreocorticotrophic hormone and corticosterone and abnormally low sensitivity to negative feedback induced by serum corticosterone indicate a dysfunction of the hypothalamic-pituitary- adrenal axis. We hypothesize that hypothalamic dysfunction is responsible for the phyenotypic changes in the behavioral, metabolic, and endocrine abnormalities associated with the Zucker obese rats. We also hypothesize that such hypothalamic dysfunction can be corrected by transplantation of lean fetal hypothalamic tissue into the third ventricle of these rates. To test three hypotheses, we will perform the following experiments:
Specific Aim 1. To further characterize the transplant model by determining effects of transplanting different amount of hypothalamic tissue, the part of the hypothalamus, and the site of transplantation on the development of obesity and serum levels of triglyceride, cholesterol, insulin, ACTH, and corticosterone in the Zucker obese rates (falfa) following transplantation.
Specific Aim 2. We showed that transplantation of lean fetal hypothalamus into the third ventricle of the Zucker obese rat resulted in a marked reduction in plasma triglyceride and yet a marked elevation of plasma cholesterol. Using density ultracentrifugation, we will characterize the lipoproteins present in plasma following hypothalamic transplantation. The proposed studies are important because it will provide new and pertinent information regarding obesity, in particular genetic obesity. The proposed studies are of clinical relevance and they may provide useful information in the management of obesity. Lastly, the proposed studies will complement the exciting genetic studies being conducted in numerous laboratories regarding obesity genes and how they regulate body weight.
