Impacts of Maternal Obesity on Reducing Leptin Signaling in the Pituitary and Its Role in Depressing the GH/IGF1 Axis, Resulting in Insulin Dysregulation and Increased Adiposity in Adult Offspring Obesity is a major health concern, and the world is facing a global epidemic of obesity with increasing rates. It is considered a disease state in itself, but more importantly, it is also a major risk factor for other serious diseases including type II diabetes, hypertension, non-alcoholic fatty liver disease, and coronary heart disease. Currently, obesity affects more than one third of the women of reproductive age in the United States. Not only does obesity during pregnancy lead to increased maternal health concerns, it is linked to increases in adiposity and components of the metabolic syndrome in their offspring. Both human epidemiological studies and animal models of maternal obesity have provided strong evidence for the association of maternal overnutrition/obesity during pregnancy with abnormal fetal organ development, increased offspring adiposity and insulin resistance. However, the mechanisms mediating the alterations in offspring metabolic dysfunction born to obese mothers are yet to be elucidated. Leptin, a hormone mainly produced by adipocytes, is well-known for its effect on appetite control in the hypothalamus; however, recent studies suggest that it may also play important roles in the pituitary regulating body composition. This dissertation mainly focuses on the possible role of pituitary leptin signaling in mediating the phenotype of increased adult offspring adiposity and insulin resistance programmed by in utero exposure to maternal overnutrition/obesity. Further, we investigated the effect of an early pregnancy dietary intervention on both mothers and fetuses in a sheep model of maternal obesity in search of a potential intervention strategy for obese human pregnancies. In the first experiment, we evaluated the impact of maternal obesity on offspring weight gain, adiposity and insulin resistance during an ad libitum feeding trial in adulthood. We found that both male and female offspring of overnourished/obese mothers (MO) had increased appetite, weight gain, percentage body fat and insulin resistance compared with offspring born to control fed mothers (CON). Then, we evaluated the hormonal profiles of male offspring at necropsy at the end of the feeding trial, and further determined the role of leptin signaling utilizing relevant tissue samples from the male offspring. We confirmed that pituitary leptin signaling was reduced and was associated with down-regulation of the growth hormone (GH)/insulin-like growth factor 1 (IGF1) axis in MO offspring compared with CON offspring. In the second experiment, we have evaluated the effect of reducing maternal global food intake in obese pregnant ewes to a maintenance level at day 28 of gestation which is equivalent to d̃ay 50 in human pregnancy. The results of this study are consistent with the concept that reducing maternal diet of obese overfed ewes to requirements from early gestation can prevent subsequent alterations in fetal growth, adiposity and glucose-insulin dynamics. Given the relative importance of maternal metabolic parameters on offspring development in humans, and the similarities between our ovine model data and those from obese pregnancies in humans, we suggest that our model could potentially lead to a better understanding of the specific control mechanisms involved. |
