Meeting Abstract

46.1  Saturday, Jan. 5  A Unifying Cell-Molecular Mechanism for the Co-evolution of Breathing, Locomotion and Metabolism TORDAY, John/S*; REHAN, Virender/K; UCLA; UCLA jtorday@labiomed.org

We have identified a unifying, functional genomic, cell-molecular mechanism for the long-speculated co-evolution of breathing, locomotion and metabolism. Fluid distension of the developing mammalian lung determines the cell-molecular “switch” from the epithelial-mesenchymal signaling by Sonic Hedgehog/Wingless/int, which determines the myofibroblast phenotype, to the Parathyroid Hormone-related Protein(PTHrP)/PTHrP receptor signaling, which determines alveolar development (Torday JS,Rehan VK. Pediatr Research 2006). PTHrP stimulation of the lung fibroblast-derived metabolic hormone leptin determines the cellular composition of the gas exchange unit of the lung alveolus, namely the lipofibroblast, type II cell, and endothelium, which coordinately mediate lipid trafficking for surfactant synthesis. These cell signaling features are expressed throughout vertebrate phylogeny, from the swim bladder of fish, where tidal inflation and deflation mediate co-adaptation for buoyancy and feeding, to the regulation of alveolar homeostasis in amphibians, reptiles, birds and mammals, suggesting that selection pressure for these evolved traits is mediated through cell-cell signaling mechanisms for alveolar homeostasis. Since Denver et al had shown that leptin stimulates limb generation by Xenopus laevis (Crespi and Denver, PNAS 2006), we tested the effect of leptin on lung development in stage 55-58 tadpoles. Leptin significantly increased surfactant phospholipid synthesis by cultured tadpole lung (47%,p<.001), indicating that leptin coordinates development of limbs and lung, demonstrating mechanistically how metabolism, respiration and locomotion may have co-evolved.