Development of metabolic systems.

In the normal adult rodent and primate, arcuate nucleus (ARH) neurons function as conduits for transmitting metabolic hormonal signals into the hypothalamic circuitry that modulates feeding and energy expenditure. We and others have shown that ARH projections do not fully develop until the 3rd postnatal week in the rodent. This is in stark contrast to the nonhuman primate (NHP) in which ARH projections develop during the 3rd trimester of pregnancy. This species difference suggests that maternal diet and health are likely key factors for the development of ARH projections in the primate, whereas the postnatal environment (i.e., diet) would be more important in the rodent. Furthermore, pertubations in these circuits during critical periods of development may have long-term consequences on feeding behavior and body weight management. Our group has used a rat model of overfeeding and underfeeding specifically during the postnatal period to begin to investigate the metabolic adaptions that may cause developmental abnormalities in the hypothalamic circuitry. While the overfed animals become obese as adults and the underfed maintain a lean phenotype, both models display low basal insulin and IGFII levels as adults. Furthermore, both models have abnormal expression of several key genes in peripheral metabolic tissue that are suggestive of changes in sympathetic outflow. Human studies show that gestational diabetes can also contribute to the development of obesity and diabetes in children; however, the mechanism is unknown. Since the critical periods for the development of hypothalamic circuits are different between rodents and primates our group has begun studies using NHP model to determine if maternal obesity/diabetes causes abnormalities in the development of metabolic systems, including the brain, in the offspring. To do this we have placed female NHPs on either a control diet or a high fat/calorie diet to induce obesity and diabetes. We have characterized the onset of insulin resistance and hyperleptinemia in these animals over the last 2(1/2) years and have collected offspring. Ongoing studies will investigate the metabolic abnormalities in these offspring.