Strategies for the treatment and prevention of obesity and its associated pathologies will depend upon our understanding of the physiologic pathways regulating energy balance. Some obesity may be caused by genetic mutations that affect these pathways; such mutations are known to exist in rodents and provide investigators with useful models for contrasting normal and aberrant regulation of energy balance. Our long-term goal is to develop a conceptual model that explains the impact of genetic mutations on the energy balance regulatory pathway. Most rodent obesity mutants appear to be recessive, however, the rat obesity gene fatty (fa), shows remarkable variation in recessivity during early development; an observation that appears to be novel for any mammalian gene. The objective of this research is to determine the physiologic mechanisms responsible for this change in recessivity. Our first objective is to test a model that explains the development of fa recessivity.
Three specific aims are proposed : A) Test the hypothesis that fa genotype effects on plasma insulin and growth are codominant when corticosterone levels are low and become increasingly recessive as corticosterone levels increase. B) Determine whether fa genotype effects can be altered by changing the endocrine environment during early life. These experiments will test three hypotheses: B.1) fa genotype effects can be altered from codominant to recessive by supplementation with corticosterone from days 4-8 of life, B.2) fa genotype effects can be altered from recessive to codominant by blocking the glucocorticoid receptor with mifepristone early in life from day 8- 16 of life, B.3) fa genotype effects on the development of increased adiposity can be blocked by induction of chemical diabetes from days 4-8 of life. C) Contrast fa genotype effects on sympathetic activation of brown adipose tissue to fa genotype effects on plasma insulin. Two experiments will test the hypothesis that fa genotype effects on sympathetic activation of brown adipose tissue are codominant while effects on insulin mediated responses are recessive. Our second objective is to identify a step in the insulin regulatory branch of the physiologic pathway disrupted by fa. This objective will contribute to identifying the step in this pathway that converts the codominant effect of fa genotype on plasma insulin to recessive effects. The fourth specific aim will evaluate a candidate, neuropeptide Y, for evidence that it contributes to the development of the recessive component of fa genotype effects. These experiments will use a molecular genetic model that allows fa genotype to be accurately measured, and an improved statistical model that allows investigators to investigate the relationship between genotype and the developing phenotype. This statistical model allows the effects of fa genotype to be efficiently isolated and separated into codominant and recessive components. This represents a new approach that unites molecular, physiologic and quantitative genetics techniques to understand the conversion of fa genotype into a recessive obese phenotype.
