Leptin stimulates Xenopus lung development: evolution in a dish J.S. Torday, a,Ã Kaori Ihida-Stansbury, b and Virender K. Rehan c a Department of Pediatrics, Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA 90502, USA b Institute for Medicine & Engineering, University of Pennsylvania, 1010 Vagelos Research Labs, 3340 Smith Walk, Philadelphia, PA 19104, USA c Department of Pediatrics, Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA 90502, USA Ã Author for Correspondence (email: jtorday@labiomed.org) SUMMARY The transition from uni- to multicellular organisms required metabolic cooperativity through cell--cell interactions mediated by soluble growth factors. We have empi- rically 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 develop- mentally 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 physio- logic 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. INTRODUCTION Pleiotropy, the effect of a common agent on multiple tissues and organs to integrate development, homeostasis, regener- ation, and aging, has been suggested as a mechanism of evo- lution, but to date there are few, if any, examples showing how pleiotropy may have affected structure or function con- sistently with evolution (Finch and Rose 1995). Leptin and its receptor are highly conserved members of the class-I Helical Cytokine Family (Huising et al. 2006). Leptin has been shown to affect the growth and differentiation of a wide variety of biological systems, including the lung (Kirwin et al. 2006), vasculature (Wolk et al. 2005), bone (Fu et al. 2006), and the central nervous system (Louis and Myers 2007). More re- cently, leptin has been shown to stimulate both food intake and limb development in Xenopus tadpoles (Crespi and Den- ver 2006). The Xenopus tadpole lung also expresses the leptin receptor (Crespi and Denver 2006), prompting us to suggest that leptin may also affect lung development, thus providing a novel mechanistic link between metabolism, locomotion, and respiration that could mediate evolutionary selection pressure. Both lung evolution and development are characterized by progressive increases in the gas exchange surface area-to-blood volume ratio (Maina 2000). These processes are characterized by decreasing epithelial cell height, decreasing basement mem- brane thickness, and increasing surface area for gas exchange. How these processes evolved to accommodate selection pres- sure for metabolic cooperativity remains speculative. The coevolution of metabolism, respiration, and locomo- tion has been documented and commented on repeatedly (Duncker 2004; Hillenius and Ruben 2004), yet there is no integrating mechanism to experimentally test these relation- ships. Crespi and Denver (Crespi and Denver 2006) have provided evidence that the metabolic hormone leptin stimu- lates Xenopus laevis tadpole limb development, providing a mechanistic link between metabolism and locomotion for the first time. They also highlighted the presence of the leptin receptor in a wide variety of tadpole organs (Crespi and Denver 2006), including the lung. Our laboratory has previ- ously shown that leptin is an important intrinsic determinant of the structural and functional development and homeostasis of the mammalian lung (Torday and Rehan 2002; Torday et al. 2002), mechanistically linked to parathyroid hormone- related protein, a stretch-regulated gene that determines the development of a wide variety of tissues and organs, including the skeleton, skin, and lung (Karaplis et al. 1994). All of these structures were critical for the evolution of land vertebrates. Based on the observation that leptin stimulates limb devel- opment, and the expression of the leptin receptor in the lungs of Xenopus laevis tadpoles (Crespi and Denver 2006), we 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 EVOLUTION & DEVELOPMENT 11:2, 218–223 (2009) DOI: 10.1111/j.1525-142X.2009.00321.x & 2009 The Author(s) Journal compilation & 2009 Wiley Periodicals, Inc. 218 EDE 321 B Dispatch: 24.1.09 Journal: EDE CE: Journal Name Manuscript No. Author Received: No. of pages: 6 PE: xx EDE 321 (BWUS EDE 321.PDF 24-Jan-09 12:19 529435 Bytes 6 PAGES n operator=jnm.Christina)