The adipokine leptin has been shown to be critical in appetite regulation and energy homeostasis. With the leptin receptor expressed ubiquitously throughout the body and recently discovered expression in the anterior pituitary, little is known about the role leptin has on cell specific pituitary function. Work from our lab has demonstrated that leptin receptor deletion specifically in somatotropes of mice results in increased fat mass, decreased GH protein and mRNA expression, sex specific responses in PRL and TSH cells, and dysregulates pituitary function as early as the neonatal stage. This has led us to investigate how the natural loss in leptin signaling affects pituitary function. This body of work explores two endogenous means of disrupting leptin signaling: 1) transient loss of leptin signaling through acute and prolonged fasting of male mice and 2) the use of maternal undernutrition to alter the neonatal leptin surge and the response by the pituitary of adult offspring on a high fat diet. With the fasting studies, male mice were fasted for 6, 12, 24, and 48 h. I observed a decrease in serum leptin at all time points, where ghrelin was elevated only with the 48 h fast. There was a biphasic response by somatotropes, where serum GH levels decreased with the 24 h fast and was elevated with the 48 h fast. Leptin and ghrelin induced changes in Ghrhr and Ghsr mRNA expression may account for the GH secretory response. The maternal undernutrition studies required that I develop a model suitable for our FVB mice. I devised a mild, 20%, maternal caloric restriction model that resulted in a shifted, premature neonatal leptin curve. The mild maternal undernutrition resulted in altered postnatal GH secretion at PND1 and reduced IGF1 at PND16. There were sex specific responses by offspring with the maternal undernutrition. Males from undernourished dams remained smaller in terms of length when compared to males of nourished dams, where length in female offspring was not significantly changed by maternal nutritional status. When challenged by a HF diet, male offspring of undernourished dams did not gain significant weight compared to control fed males and were therefore protected against diet induced weight gain. Gh, Ghrhr, and Ghsr mRNA expression in the pituitary was regulated differently based on maternal nutrition and sex of offspring. Together these studies demonstrate a physiological role of leptin on somatotrope function, in a sex specific manner, in terms of transient loss as seen in adults and due to altered expression in early programming of mice.
|Advisor:||Childs, Gwen V.|
|Commitee:||Diekman, Alan, MacNicol, Angus, MacNicol, Melanie, McGehee, Robert E., Jr.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 82/4(E), Dissertation Abstracts International|
|Subjects:||Endocrinology, Neurosciences, Nutrition|
|Keywords:||Fasting, Growth hormone, Leptin, Leptin surge, Maternal undernutrition, Pituitary, Caloric restriction|
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