The transition from uni- to multicellular organisms required metabolic cooperativity through cell-cell interactions mediated by soluble growth factors. We have empirically demonstrated such an integrating mechanism by which the metabolic hormone leptin stimulates lung development, causing the thinning of the gas exchange surface and the obligate increase in lung surfactant synthesis. All of these processes have occurred both phylogenetically and developmentally during the course of vertebrate lung evolution from fish to man. Here we show the integrating effects of the environmentally sensitive, pleiotropic hormone leptin on the development of the Xenopus laevis tadpole lung. The process described in this study provides a mechanistically integrated link between the metabolic regulatory hormone leptin and its manifold downstream effects on a wide variety of physiologic structures and functions, including locomotion and respiration, the cornerstones of land vertebrate evolution. It provides physiologic selection pressure at multiple levels to progressively generate Gene Regulatory Networks both within and between organs, from cells to systems. This model provides a cipher for understanding the evolution of complex physiology.