Leptin does not influence surfactant synthesis in fetal sheep and mice lungs

Abstract

In the fetus, leptin in the circulation increases at late gestation and likely influences fetal organ development. Increased surfactant by leptin was previously demonstrated in vitro using fetal lung explant. We hypothesized that leptin treatment given to fetal sheep and pregnant mice might increase surfactant synthesis in the fetal lung in vivo. At 122-124 days gestational age (term: 150 days), fetal sheep were injected with 5 mg of leptin or vehicle using ultrasound guidance. Three and a half days after injection, preterm lambs were delivered, and lung function was studied during 30-min ventilation, followed by pulmonary surfactant components analyses. Pregnant A/J mice were given 30 or 300 mg of leptin or vehicle by intraperitoneal injection according to five study protocols with different doses, number of treatments, and gestational ages to treat. Surfactant components were analyzed in fetal lung 24 h after the last maternal treatment. Leptin injection given to fetal sheep increased fetal body weight. Control and leptin-treated groups were similar in lung function (preterm newborn lamb), surfactant components pool sizes (lamb and fetal mice), and expression of genes related to surfactant synthesis in the lung (fetal mice). Likewise, saturated phosphatidylcholine and phospholipid were normal in mice lungs with absence of circulating leptin (ob/ob mice) at all ages. These studies coincided in findings that neither exogenously given leptin nor deficiency of leptin influenced fetal lung maturation or surfactant pool sizes in vivo. Furthermore, the key genes critically required for surfactant synthesis were not affected by leptin treatment.

Regulation of fetal lung development in response to maternal overnutrition

“…Leptin has a wide range of physiological functions, such as regulation of satiety, energy metabolism, bone formation and reproduction. 107 In vitro leptin treatment of fetal rat lung explants increases synthesis of surfactant lipids and proteins. 108 This is supported by an in vivo study of maternal leptin treatment of pregnant rats, in which a 14% increase in relative lung weight was observed accompanied by an increase in the expression of surfactant proteins and the number of Type II AEC.…”

“…109 In contrast with these findings, injection of leptin directly into the sheep fetus before a preterm Caesarean section resulted in an increased body weight:lung weight ratio compared with the controls, with no accompanying change in surfactant protein or phospholipid content. 107 The difference in lung maturation indices between these two studies may be a result of differences in the dose, duration or route of leptin administration. Given that overnutrition leads to increased plasma leptin concentrations in pregnant ewes, 106 it is possible that production of surfactant phospholipids as well as surfactant protein synthesis may be affected in pregnancies complicated by maternal obesity.…”

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

“…Peroxisome proliferator-activated receptor-g (PPARg) signaling is important in lipofibroblast differentiation (13,14), and PPARg agonists can reverse lipofibroblast to myofibroblast differentiation and restore alveolar development in murine and rat models (10,15). The only described signaling pathway upstream of PPARg that promotes fibroblast lipid accumulation is the parathyroid-related peptideleptin axis (16), although a recent report questioned the importance of lipofibroblast leptin signaling (17). To understand the key events in alveolar development, a broader understanding of the endogenous factors that promote lipofibroblast differentiation is needed.…”

What is the identity of fibroblast-pneumocyte factor?

“…However, there is some controversy over the role of leptin in lung development. For example, other investigators have failed to identify an effect of leptin on fetal mouse or fetal sheep lung surfactant development, and found normal surfactant levels in ob/ob neonatal mice at all ages (55). Further, the proposed model of leptin regulating fetal lung maturation is closely tied to the function of pulmonary lipofibroblasts; while this cell type exists in rodent lungs there remains controversy regarding the existence of these cells in human lungs (56–58), adding uncertainty regarding the importance of leptin for development of surfactant synthesis in the human lung.…”