Investigators:
- Vicky L. Funanage, PhD
- Sandra Hassink, MD
Background
Leptin is a hormone that plays a critical role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. Defects in leptin production cause severe hereditary obesity in rodents and humans. In addition to its effects on body weight, leptin has a variety of other functions, including the regulation of hematopoiesis, angiogenesis, wound healing, and the immune and inflammatory response.
A collaboration with Sandra Hassink, M.D., Director of the Weight Management Program at Nemours Children's Clinic-Wilmington, has shown that leptin is produced by both the placenta and mammary gland, indicating the importance of leptin in fetal and neonatal growth. In addition, results indicate that leptin augments surfactant production in fetal lung, and a patent application has been filed for the use of leptin in treatment of respiratory distress syndrome in infants, children, and adults. A relatively new collaboration has begun with Thomas Shaffer, Ph.D., Director of the Nemours Research Lung Center whereby the upregulation of surfactant proteins by various agents in the fetal lamb is being investigated as an alternative treatment in premature infant respiratory distress syndrome. A Nemours patent (U.S. Patent No. 6,475,984) was awarded last year for the administration of leptin, and another patent is pending regarding the use of leptin as a method for treatment of respiratory distress syndrome.
What We're Doing
Pulmonary alveolar type II cells synthesize and secrete phospholipids and surfactant proteins (SP-A, SP-B, SP-C). In most mammalian species, the synthesis of phospholipids and proteins of lung surfactant increases with fetal lung maturation, which occurs late in gestation. The expression of the placental hormone, leptin, increases with advancing gestational age, suggesting that leptin regulates some aspect of developmental growth in the fetus. We hypothesize that leptin influences maturation of fetal lung development.
Recent studies on the hormone leptin have outlined its role in energy homeostasis, regulating such diverse processes as satiety, fetal and neonatal growth, and immune function. In most mammalian species, the synthesis of lipids and proteins of lung surfactant increases with fetal lung maturation, which occurs late in gestation. Leptin-deficient ob/ob mice have a specific respiratory phenotype of alveolar hyperventilation and chronic hypercapnia. We propose that leptin is important for lung growth and/or maturation and that the lack of leptin exposure late in pregnancy when the type II alveolar cells are maturing and producing surfactant could contribute to the respiratory distress suffered by many premature infants. Since leptin has been found in amniotic fluid, we hypothesized that leptin may have a direct effect on type II alveolar cell maturation and growth.
Some of What We've Found
Using both rat fetal lung explant cultures and isolated fetal type II alveolar cells in culture, we demonstrate that physiological concentrations of leptin (1 and 10 ng/ml) increase the mRNA levels of surfactant proteins A, B, and C compared to 18S rRNA. To determine whether leptin exerts similar effects in vivo, we administered leptin antenatally to pregnant rats and compared its effects to that of dexamethasone, a known mediator of fetal lung development. Antenatal treatment with leptin for two days increased the average weight of the fetal lungs in relation to their body weight. Histologic analysis revealed that the increase in fetal lung weight was accompanied by an increase in the number of type II alveolar cells. Collectively, these results suggest that leptin is a cytokine regulator of rat fetal lung maturity.