Leptin and the control of pulmonary maturation before birth

Lead Research Organisation: University of Cambridge
Department Name: Physiology Development and Neuroscience

Abstract

Normal development of the fetal lungs is essential for newborn babies to be able to breathe at delivery. Hormones produced by the fetus are important for a range of maturational changes that occur in the lungs of the fetus to prepare it for the transition from the womb to the outside world. Premature delivery before these maturational changes have taken place leads to respiratory disease in the newborn. Leptin is a hormone that is known to regulate appetite and metabolism in adult life, but its functions in the fetus are poorly understood. Leptin production is increased in the fetus after glucocorticoid treatment which is commonly used to promote lung maturation in fetuses at risk of preterm delivery. Furthermore, there is some evidence from laboratory studies on fetal lung tissue that leptin may influence lung development before birth. In an animal model, this project will investigate (a) the control of leptin activity in fetal lungs and (b) the effect of leptin on lung development. It will measure leptin production and receptor expression in fetal lungs at a range of gestational ages and after glucocorticoid treatment, and will determine several aspects of lung structure and function in animals treated with leptin before birth. The findings of this project will improve our understanding of the control of lung development in the fetus and will provide important information about the consequences of premature birth. Leptin may be a potential therapeutic agent in the treatment and prevention of respiratory disease in the premature infant at birth and in adult life.

Technical Summary

Glucocorticoids are essential for normal pulmonary maturation in utero and respiratory function at birth, although the extent to which their actions are mediated by leptin is unknown. The hypothesis of this project is that developmental and glucocorticoid-dependent increments in circulating leptin are responsible for aspects of lung maturation in the fetus near term. Therefore, the project will ask three research questions: 1. What are the normal developmental changes in leptin and leptin receptor expression in fetal lungs during late gestation? 2. Is pulmonary leptin and leptin receptor expression in utero upregulated by endogenous and synthetic glucocorticoids? 3. What are the effects of leptin administration on indices of pulmonary development in the fetus? Blood and a variety of tissues, including lungs, will be collected from sheep fetuses after experimental manipulation of leptin and glucocorticoid concentrations during late gestation. Various indices of pulmonary structure and function will be determined including alveolar number, surface area and diffusion distance, and the gene and protein expression of surfactant proteins and vascular endothelial growth factors. The project will provide valuable information about the mechanisms responsible for the hormonal control of pulmonary development before birth, with important implications for fetal, neonatal and adult health. A greater understanding of the basic science underlying normal development of the fetal lungs is essential for the future progress of therapeutic and preventative strategies for the consequences of prematurity. Indeed, the findings may provide a novel mechanism for the maturational actions of antenatal glucocorticoid therapy. Furthermore, since the intrauterine environment influences the development of the lungs both before and after birth, these findings may provide a mechanism for the developmental programming of respiratory function in adult life.

Planned Impact

The primary beneficiaries from the proposed research will include (a) researchers in fetal and neonatal physiology, intrauterine programming, mammalian endocrinology and respiratory physiology, (b) obstetricians and paediatricians caring for preterm pregnancies and infants, (c) premature babies and mothers at risk of preterm delivery, and (d) pharmaceutical organisations who may translate the findings into clinical practice. Furthermore, the economic and social consequences of prematurity mean that there are wider implications of the research for society in both the short and longer term. The project will provide valuable and novel information on the endocrine control of lung development before birth. A greater understanding of the basic science underlying normal development of the fetal lungs is essential for the future progress of therapeutic and preventative strategies for the consequences of prematurity. Indeed, the project may elucidate leptin as a mechanism by which endogenous and synthetic glucocorticoids promote lung maturation and as an important potential therapeutic agent for preterm infants. Lung development before birth also has long-term consequences for a number of adult pathologies, such as asthma and chronic lung disease. Therefore, understanding the mechanisms underlying the control of lung development will have significant implications not only for fetal and neonatal health, but also for the development of preventative strategies for respiratory diseases in adult life. Current collaborative links with members of the Departments of Obstetrics and Gynaecology, Clinical Biochemistry and Paediatrics, at Addenbrooke's Hospital, Cambridge will allow dissemination of results at local special interest groups and departmental seminars. For example, the applicant is a member of the local Perinatal Research group of clinicians and basic scientists who meet on a regular basis to discuss recent research and clinical findings. Furthermore, as an executive committee member of the Neonatal Society, Dr Forhead has links with a number of obstetricians and neonatalogists that will provide useful in the potential translation of these findings to clinical practice. The University of Cambridge has a department concerned specifically with the commercial exploitation of research findings (Cambridge Enterprise, part of the University Research Services Division) and they would be consulted where necessary. Due to the use of animals in this project, care needs to be taken when communicating detailed research information to the public. However, the applicant actively promotes understanding of physiology more generally and participates in the London International Youth Science Forum and the annual departmental open day as part of the University of Cambridge Science Festival. She is also involved in a number of college-based events which promote the Natural Sciences course to school children and pupils in higher education.

Publications

10 25 50
 
Description The project has confirmed the original hypothesis that developmental and glucocorticoid-dependent changes in the hormone leptin may be responsible for aspects of lung maturation in the fetus near term. Our data show that leptin receptor mRNA is present in ovine fetal lungs from at least 100d of gestation and increases towards term, in association with pre-partum increments in plasma cortisol and leptin, and adipose leptin mRNA. Naturally-occurring and synthetic glucocorticoids upregulated leptin receptor mRNA levels in fetal lungs. Leptin receptor protein was localised to Type II pneumocytes that secrete surfactant; pulmonary expression of leptin receptor protein decreased with gestational age and glucocorticoid treatment which may reflect cell-specific localisation of the receptor. Ovine fetal lungs do not appear, however, to be a site of leptin synthesis.

Leptin infusion in utero had maturational effects on pulmonary function (by measurement of static lung complicance) and structure, and increased expression of genes associated with surfactant production. The increase in relative heart weight seen in the leptin-treated fetuses warrants further investigation.
Exploitation Route A greater understanding of the basic science underlying normal development of the fetal lungs is essential for the future progress of therapeutic and preventative strategies for the consequences of prematurity. Indeed, the findings contribute to a novel mechanism for the maturational actions of antenatal glucocorticoid therapy. Furthermore, since the intrauterine environment influences the development of the lungs both before and after birth, these findings may provide a mechanism for the developmental programming of respiratory function in adult life.

During this project, a variety of fetal and placental tissues were collected from the saline and leptin-treated fetuses at post-mortem. These tissues are currently and will be used in collaborative projects and as part of other grant proposals.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The findings from this basic science project provide data that rethinks the control of fetal maturation, of the lungs and other tissues. The role of leptin in the fetus has been under-investigated and our studies have shown that it has important physiological significance before birth. The impact of this work for clinical practice may emerge when the findings are published fully.
 
Description Research Excellence Award
Amount £10,000 (GBP)
Organisation Oxford Brookes University 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 08/2018
 
Description Dominique Blache 
Organisation University of Western Australia
Country Australia 
Sector Academic/University 
PI Contribution Provision of plasma samples for analysis; generation of other data for publications; co-authorship of publications
Collaborator Contribution Measurement of plasma hormone concentrations
Impact Publications: doi: 10.1210/en.2015-1729 doi: 10.1371/journal.pone.0136115 doi: 10.1677/JOE-10-0360 doi: 10.1113/jphysiol.2007.149237 PMID: 17495000
Start Year 2007
 
Description Gordon Smith, Steve Charnock-Jones 
Organisation Addenbrooke's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Provision of tissue from experimental animal groups; provision of primary data for analysis; collaboration on data analysis and publications
Collaborator Contribution Expertise in molecular biology techniques; assistance with design of ovine-specific probes
Impact Publications: doi: 10.1210/en.2015-1729 doi: 10.1371/journal.pone.0136115 doi: 10.1152/ajpgi.00397.2010 doi: 10.1210/jc.2010-0037 PMID: 18091346
 
Description Sean Limesand 
Organisation University of Arizona
Department School of Animal and Comparative Biomedical Sciences
Country United States 
Sector Academic/University 
PI Contribution My PhD student visited the laboratory of Sean Limesand to carry out collaborative research on the control of pancreatic islet development by leptin, insulin and thyroid hormones. I provided financial support for the experiments in vitro which complemented the experiments in vivo performed in my laboratory in the UK.
Collaborator Contribution Sean Limesand and his colleagues carried out a series of experiments in vitro. They provided expertise, financial support and training for my PhD student.
Impact One paper has been published using data from this collaboration (PMID: 28144955, DOI: 10.1113/JP273555).
Start Year 2013
 
Description Stuart Lanham, Richard Oreffo 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of bones from fetal sheep for analysis; generation of other data for publication; co-authorship in publications
Collaborator Contribution Measurement of indices of bone morphology
Impact Publications doi: 10.1530/JOE-11-0138 and doi: 10.1152/ajpregu.00351.2017.
Start Year 2009
 
Description Centre for Trophoblast Research, Principal investigator lecture (Cambridge) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact I was invited to present a review of my research (Principal Investigator Presentation) at the away-day for the Centre for Trophoblast Research in Cambridge, September 2012. My talk was entitled 'Preparing for birth: role of hormones in fetal maturation' and led to discussions afterwards.
Year(s) Of Engagement Activity 2012
 
Description Guest lecturer on Diploma of Bovine Reproduction course (Liverpool) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I was invited to contribute as a guest lecturer to the Diploma of Bovine Reproduction, a professional qualification for veterinary practitioners, at the University of Liverpool. My talk was entitled 'Developmental programming: long term consequences of intrauterine nutrition' and was followed by a workshop on the implications of programming for the cattle industry. The concept of developmental programming and the importance of the intrauterine environment for future well-being is a relatively new idea for veterinary professionals and they welcomed the opportunity to discuss the possible consequences for livestock production and health.
Year(s) Of Engagement Activity Pre-2006,2006,2009,2011,
 
Description Socio-Legal Group workshop (Cambridge) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was invited to contribute to the meeting of the Cambridge Socio-Legal Group in the Faculty of Law, Cambridge. A two-day workshop of international experts from science, medicine, law, ethics and sociology met to discuss aspects of birth. My talk and published paper was entitled 'The consequences for preterm infants of antenatal glucocorticoid treatment'. The paper was published in 'Birth Rites and Rights', Hart Publishing as a legal text-book.
Year(s) Of Engagement Activity 2010
 
Description Talk at Human Nutrition Research Centre (Newcastle) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact I was invited to give a talk about my research to the Human Nutrition Research Centre at the University of Newcastle in February 2015. My talk was entitled 'Fat fetuses: role of leptin as a maturational signal before birth'. The audience comprised academic staff, researchers, technicians and postgraduate and undergraduate students. We discussed the translational use of the findings more widely. During my visit, I was able to meet with other researchers to discuss their work and collaborative opportunities.
Year(s) Of Engagement Activity 2015