Effects of leptin deficiency on postnatal lung development in mice

Abstract

Leptin modulates energy metabolism and lung development. We hypothesize that the effects of leptin on postnatal lung development are volume dependent from 2 to 10 wk of age and are independent of hypometabolism associated with leptin deficiency. To test the hypotheses, effects of leptin deficiency on lung maturation were characterized in age groups of C57BL/6J mice with varying Lep(ob) genotypes. Quasi-static pressure-volume curves and respiratory impedance measurements were performed to profile differences in respiratory system mechanics. Morphometric analysis was conducted to estimate alveolar size and number. Oxygen consumption was measured to assess metabolic rate. Lung volume at 40-cmH(2)O airway pressure (V(40)) increased with age in each genotypic group, and V(40) was significantly (P < 0.05) lower in leptin-deficient (ob/ob) mice beginning at 2 wk. Differences were amplified through 7 wk of age relative to wild-type (+/+) mice. Morphometric analysis showed that alveolar surface area was lower in ob/ob compared with +/+ and heterozygote (ob/+) mice beginning at 2 wk. Unlike the other genotypic groups, alveolar size did not increase with age in ob/ob mice. In another experiment, ob/ob at 4 wk received leptin replacement (5 microg.g(-1) x day(-1)) for 8 days, and expression levels of the Col1a1, Col3a1, Col6a3, Mmp2, Tieg1, and Stat1 genes were significantly increased concomitantly with elevated V(40). Leptin-induced increases in V(40) corresponded with enlarged alveolar size and surface area. Gene expression suggested a remodeling event of lung parenchyma after exogenous leptin replacement. These data support the hypothesis that leptin is critical to postnatal lung remodeling, particularly related to increased V(40) and enlarged alveolar surface area.

Obesity and Asthma

“…Previous reports have also shown that leptin and leptin receptor are expressed in airway epithelium (24), and bronchial expression of leptin is increased in chronic obstructive pulmonary disease (25,26). Leptin seems to be involved in embryonic lung growth and maturation (27,28), and in fibroproliferative responses in the lung to bleomycin (29). Furthermore, polymorphisms in leptin and leptin receptor have been associated with differences in lung function (30,31).…”

Obesity Hypoventilation Syndrome

“…Hypercapnic OSA patients have significantly lower hypercapnic ventilatory response when compared to eucapnic OSA patients with similar leptin levels [56]. Consequently, in humans with OHS, Leptin resistance is thought to contribute to the pathophysiology in a manner similar to that described in a leptin-deficient mouse model manifested by reduction in lung volumes, compliance, abnormal respiratory muscle function, and defects in upper airway neuromechanical control [17] [61,62].…”

Asthma and Obesity - the Recent Advancements

“…Increased levels of serum leptin have been shown to be associated with asthma in obesity, and related to airway reactivity 19,20 . The deficiency of leptin may also be associated with a reduced lung volume and lesser availability of alveolar surface to facilitate gas exchange 21 . Importantly, an increased expression of leptin and adiponectin in lungs and adipose tissue of obese patients with asthma has been reported, and there was a significant correlation between leptin and airway hyper-responsiveness 22 .…”