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RESEARCH |
Departments of 1 Obstetrics and Gynecology, 2 Physiology, 3 Structural and Cellular Biology and 4 Medicine, 5 Interdisciplinary Program in Molecular and Cellular Biology and 6 Tulane National Primate Research Center, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA and 7 Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
Correspondence should be addressed to M C Henson, Department of Obstetrics and Gynecology (SL-11), Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, Louisiana 70112-2699, USA; Email: henson{at}tulane.edu
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Introduction |
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In addition to these roles, leptin has also been associated with the regulation of pulmonary development and respiration. Thus, in the mouse, leptin receptor mRNA has been detected in the lungs of fetuses (Hoggard et al. 1997). Specific leptin-binding sites in the pulmonary parenchyma and bronchiolar epithelium bind purified radio-labeled analog and leptin receptor expression has been demonstrated between birth and adulthood (Dal Farra et al. 2000). Receptors are also expressed in both normal human lung and the SQ-5 human lung squamous cancer cell line. SQ-5 cell proliferation was enhanced following co-incubation with recombinant human leptin, suggesting a receptor-mediated effect (Tsuchiya et al. 1999). In the ob/ob mouse, respiratory anomalies that are common with the obese phenotype (tachypnea, decreased lung compliance and aberrant respiratory muscle adaptations) were attenuated following prolonged leptin administration (Tankersley et al. 1998). Similarly, in wild-type mice that were obese merely as a consequence of their high-fat diet, respiratory depression was alleviated by leptin treatment (O’Donnell et al. 1999).
Insufficient maturation of the fetal lungs, a condition that can be characterized by the production of inadequate amounts of pulmonary surfactant by epithelial type II cells, is a leading cause of human neonatal morbidity and mortality following premature birth. In the term infant, an increase in cortisol prompts the differentiation of type II cells and consequently, surfactant synthesis (Bolt et al. 2001). However, in preterm infants, surfactant levels are insufficient and pulmonary insults lead to acute lung injury and in some cases, chronic lung disease. Surfactant production is also modulated by soluble growth factors that mediate epithelial mesenchymal interactions. In this capacity, Torday et al. (2002), reported that leptin was expressed by fibroblasts and that leptin receptor was expressed by type II cells in fetal rat lung, suggesting a paracrine signaling mechanism in developing pulmonary tissue. They later concluded that leptin plays a direct role in enhancing surfactant production (Torday & Rehan 2002), a potential recently reiterated by Vlahakis & Hubmayr (2003). Leptin receptor was also identified in fetal rabbit type II cells and additional evidence supported correlations between leptin, maturation of the pulmonary epithelium and surfactant production (Bergen et al. 2002). Evidence associating leptin with human pulmonary development has yet to be reported, necessitating the need for the current study, which to the best of our knowledge is the first to investigate the potential interrelationship of leptin with fetal pulmonary development in a primate model.
Significant differences exist between humans and non-primate species with respect to the endocrinology of pregnancy and the development of a functional maternal–fetoplacental unit (Pepe & Albrecht 1995). Therefore, in the current study we employed the baboon, a nonhuman primate that is an excellent model for human pregnancy with regard to both general gestational endocrinology (Castracane & Goldzieher 1986, Henson 1998) and LEP-related mechanisms (Henson et al. 1999, Green et al. 2000, O’Neil et al. 2001). Our primary objectives were to determine: (i) fetal serum leptin concentrations; (ii) leptin receptor ontogeny, via quantitative assessment of mRNA transcripts for leptin (LEP) in fetal lungs in early, mid and late pregnancy; (iii) the presence of leptin receptor protein in fetal pulmonary tissue; and (iv) the identities of specific cell types in fetal lung that express leptin receptor.
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Materials and Methods |
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Collection of tissues
Lung tissue was obtained from fetal baboons upon cesarean delivery, under isofluorane anesthesia, after sedation with ketamine HCl/atropine, as we have previously described (Henson et al. 1999). Surgeries were performed early in gestation (days 58–62, n = 4), at mid gestation (days 98–102, n = 4), or late in gestation (days 158–165, n = 4) (term 184 days). Fetal blood samples were collected via cardiac puncture, prior to killing (sodium pentobarbital) and the collection of fetal lung tissue. Serum was separated by centrifugation (1000 g, 10 min) and frozen at -20 °C for RIA. Tissue was flash-frozen in liquid nitrogen and stored at -70 °C, with random sections utilized for later RT-PCR and immunoblotting, or fixed in 10% formalin for immunohistochemistry.
RNA extraction and RT-PCR
Total RNA was extracted from tissues using TRIzol reagent (Invitrogen Life Technologies, Carlsbad, CA, USA), according to Chomczynski & Sacchi (1987) and Chirgwin et al. (1979), as we have adapted for use in our laboratory (Henson et al. 1998, Shi et al. 1999). All samples were treated with DNase (Invitrogen) to eliminate DNA contamination and reprecipitated with sodium acetate and 100% ethanol. Oligonucleotide primers were synthesized (Midland Reagent Company, Midland, TX, USA) for leptin (Wabitsch et al. 1996), long (LEP-RL) (Kielar et al. 1998) and short (LEP-RS) (Glasow et al. 1998) intracellular domain isoforms of the leptin receptor, and glyceralde-hyde-3-phosphate dehydrogenase (GAPDH) (Henson et al. 1998). Sequence analysis of PCR products (Biotech Core, Palo Alto, CA, USA) confirmed that primers specifically amplified regions of leptin and leptin receptor cDNAs. cDNAs were synthesized from 2 µg total RNA using the SuperScript kit (Invitrogen) and PCR was performed using HotStarTaq DNA Polymerase (Qiagen Inc., Valencia, CA, USA) in a GeneAmp PCR System 2400 (Perkin Elmer Applied Biosystems, Foster City, CA, USA) as we have described (Henson et al. 1998).
Conditions for PCR were adapted from Green et al. (2000) and O’Neil et al. (2001). They were as follows: LEP 30 cycles for amplification, denaturation at 94 °C for 60 s, annealing at 55 °C for 30 s, extension at 72 °C for 90 s; LEP-RS, 30 cycles for amplification, denaturation at 94 °C for 30 s, annealing at 51 °C for 45 s, extension at 72 °C for 30 s; LEP-RL, 35 cycles for amplification, denaturation at 94 °C for 30 s, annealing at 60 °C for 30 s, extension at 72 °C for 30 s; GAPDH, 24 cycles for amplification, denaturation at 94 °C for 30 s, annealing at 51 °C for 45 s, extension at 72 °C for 30 s. PCR products were visualized under u.v. light on 2% agarose gels with ethidium bromide. PCR reactions were accompanied by the following controls: GAPDH affirmed consistent cDNA synthesis, sterile water blanks served as a reagent control, and RNA that had not been transcribed into cDNA (absence of reverse transcriptase) was used as a control for DNA contamination, with no PCR products being evidenced in subsequent validation experiments. Following semiquantitative assessment of mRNA transcripts by comparison of PCR products with GAPDH, quantitative competitive RT-PCR was performed using the PCR MIMIC methodologies we have described (Henson et al. 1998, 1999). In this methodology, one set of primers is used to amplify both the target gene cDNA and the mimic, a non-homologous DNA fragment engineered to contain specific target gene sequences necessary for recognition by the gene specific primers for the gene of interest. The mimic DNA competes with the target cDNA for the same primers, thereby serving as an internal standard. Products were resolved by 2% agarose gel electrophoresis, and band intensities analyzed using the Alpha Imager 2000 digital analysis system (Alpha Innotech, San Leandro, CA, USA). Concentrations were expressed as attomoles/µg RNA (1 attomole = 6 x 105 molecules). All PCR experiments are subjected to replication, with the subsequent documentation of similar results required.
Immunoblotting
Total protein was extracted from fetal lung tissue using a homogenization buffer containing: 40 mmol/l KH2PO4, 10 mmol/l sucrose, 50 mmol/l KCl, 30 mmol/l EDTA, 2 mmol/l EGTA, 25 µg/ml aprotinin, 25 µg/ml leupeptin and 1 mmol/l polymethylsulfonylfluoride. The tissue homogenate was then centrifuged, supernatant collected and protein concentration quantified according to Bradford (1976). Fifty micrograms of protein were denatured, reduced and then electrophoresed on a pre-cast 4–12% gradient Bis-Tris gel (Invitrogen), before transfer to nitro-cellulose for immunoblot detection. Standards of known molecular mass (BioRad, Hercules, CA, USA) were run in adjacent lanes. Leptin receptor was detected with goat polyclonal anti-human leptin receptor (N-20; Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) at a dilution of 1:500. This antibody detects the extracellular domain of the leptin receptor, i.e. both long (LEP-RL) and short (LEP-RS) isoforms. A secondary antibody, donkey polyclonal anti-goat IgG, labeled with horseradish peroxidase (Santa Cruz) was then detected using the ECL Western blotting detection system (Amersham Pharmacia Biotech, Piscataway, NJ, USA) utilizing chemiluminescence film (Hyper-Film; Amersham). A specific blocking peptide (Santa Cruz) for the leptin receptor antibody was used effectively as a control, successfully blocking the receptor signal.
Immunohistochemistry
Immunohistochemistry was performed according to the technique of Liu et al. (1997), as adapted for use in our laboratory. Fetal baboon lung was fixed in 10% buffered formalin, paraffin imbedded and 5 µm sections cut. The sections were deparaffinized, antigen unmasked in citrate buffer and endogenous peroxidase activity quenched in 0.3% hydrogen peroxide diluted in methanol. Sections were then incubated in PBS, 0.2% fish skin gelatin (FSG) and 0.1% Triton X-100 for 20 min. Immunohistochemistry was facilitated using the Goat ABC Staining System (Santa Cruz) in a humidified chamber. Tissues were incubated in normal blocking serum for 1 h, then incubated with primary antibody for either human leptin receptor (Ob-R [N-20]; Santa Cruz) or pulmonary surfactant A (SP-A [N-19]; Santa Cruz) at a 1:25 dilution in normal blocking serum for 1 h at room temperature. Sections were again washed with PBS/FSG, then incubated with biotinylated secondary antibody. Sections were then washed with PBS/FSG then incubated with AB enzyme reagent. Hybridization was then detected using peroxidase substrate. Sections were counter-stained using Gill’s hematoxylin (2 x formulation) and mounted. Controls included sections without: (i) primary antibody and (ii) primary and secondary antibody.
RIA
Leptin concentrations were determined by RIA (Diagnostic Systems Laboratories, Inc., Webster, TX, USA), employing an antibody against human leptin. Inter- and intraassay coefficients of variation (n = 5) for leptin were less than 9.0 and 5.0% respectively, with a sensitivity of 0.5 ng/ml. The human assay had been previously validated for the baboon using a pregnant serum pool, for which serial dilutions yielded concentrations that were linear and parallel to those in human serum (Henson et al. 1999).
Statistical analysis
ANOVA, with standard post-hoc Student–Newman–Keuls tests, was employed using SigmaStat statistical analysis software, version 5.0 (SPSS, Richmond, CA, USA), to establish statistical significance between groups. Significant differences were understood to exist when P < 0.05.
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). Indeed, as quantified by competitive RT-PCR and depicted in Fig. 2A, LEP-RL transcript abundance (n = 4) increased from 0.011 ± 0.004 attomoles/µg total RNA (mean±S.E.M.), in early gestation, to 0.017 ± 0.004 in mid gestation, to 0.119 ± 0.013 in late gestation. Therefore, although LEP-RL transcript abundance in early and mid gestation was quite low, approaching the level of nondetection, concentrations in late gestation were 10- and 7-fold greater (P < 0.05) respectively. Overall, specific mRNA transcripts for LEP-RS were of greater abundance than those for LEP-RL, although a similar rate of increase was observed with respect to advancing gestation. Thus, as illustrated in Fig. 2B, LEP-RS transcript abundance (n = 4) increased from 0.069 ± 0.028 attomoles/µg total RNA in early gestation, to 0.139 ± 0.032 in mid gestation, to 0.550 ± 0.057 in late gestation. Therefore, LEP-RS transcript abundance in late gestation was approximately 4-fold greater (P < 0.05) than at mid gestation and 8-fold greater (P < 0.05) than in early gestation.
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. Leptin receptor protein could not be detected by immunoblotting in fetal lungs collected in early and mid gestation, but was detected (approximately 130 kDa, as determined by molecular mass standards – not shown) in tissues collected in late gestation.
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, leptin receptor protein in lungs from late gestation fetuses was localized by immunohistochemistry in distal pulmonary epithelial cells, including type II cells (Fig. 4C). This cell type is known to actively produce pulmonary surfactant, as evidenced by specific immunohistochemical staining of surfactant protein A (Fig. 4B) in alternate sections.
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Discussion |
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In addition to the effects of cortisol, an array of growth factors, including transforming growth factor-ß3, epithelial growth factor, tumor necrosis factor and vasointestinal peptide are involved in pulmonary development (Bolt et al. 2001). Indeed, in fetal baboons in which cortisol levels were suppressed in utero via estrogen deprivation, lung maturation proceeded unabated, suggesting the need for further studies to identify and characterize associated regulatory factors (Pepe et al. 2003). Therefore, although it is known that the maturation of type II cells is modulated by a number of soluble, low molecular weight peptides, the identity of a specific fibroblast pneumocyte factor (FPF) remains elusive. This protein is proposed to be induced by glucocorticoids, promote surfactant production, and be down-regulated by androgens (Torday et al. 2002). A number of potential commonalities exist between leptin and this putative modulator. Thus, it is interesting to note that lung development in male fetuses is somewhat delayed when compared with females in a variety of species, a phenomenon that reflects an inhibition by androgens (Provost et al. 2002). This relationship is mirrored by a similar androgen inhibition of leptin biosynthesis, an effect that is definitively linked to gender (Casabiell et al. 2001, Morash et al. 2001). Other regulatory parallels include the effects of glucocorticoids, which in addition to up-regulating the putative FPF in the lung (Bolt et al. 2001), increase leptin synthesis and release by human adipocytes (Leal-Cerro et al. 2001), and enhance leptin levels in preterm infants (Ng et al. 2002). Moreover, the co-culture of human placental trophoblast cells with glucocorticoids has been observed to enhance leptin release (Coya et al. 2001), while maternal glucocorticoid treatment resulted in an up-regulation of placental leptin receptor protein in rat pregnancy (Sugden et al. 2001). Therefore, with respect to: (i) the effects of androgens and glucocorticoids; (ii) the common tissues of origin of both leptin and the putative regulator; and (iii) the similarities in the molecular masses of leptin and the proposed FPF (Bergen et al. 2002, Torday & Rehan 2002), leptin has been suggested by Torday et al. (2002) as a logical FPF candidate.
Fetal leptin, originating in the placental trophoblast (Chen et al. 2000) or in fetal adipose tissues (Lepercq et al. 2001), is firmly associated with conceptus growth and development in a number of species, including humans (Bajoria et al. 2002, Henson & Castracane 2002, 2003, Sagawa et al. 2002). Effects are mediated in a variety of tissues via a specific leptin receptor, which is a member of the cytokine class I receptor superfamily. It exists as multiple alternatively spliced isoforms, each differing in the length of their intracellular domains (Tartaglia 1997). The long isoform (LEP-RL) is detected in various tissues, but is predominant in the hypothalamus, where it functions in the regulation of satiety and is capable of signal transduction through the activation of Janus kinase and the signal transducers and activators of transcription. A shorter isoform (LEP-RS) is predominant in peripheral tissues such as the lung and, as reported by Bjorbaek et al. (1997, 2001), contributes to leptin signaling via mitogen-activated protein kinase. In the present study, we have determined the ontogeny of leptin receptor in fetal lung during pregnancy in the baboon, a species that is a proven investigational model for the endocrinology of human pregnancy (Castracane & Goldzieher 1986, Pepe & Albrecht 1995, Henson 1998), as well as for fetal (Kotas & Kling 1979, Coalson et al. 1998, Pepe et al. 2003) and neonatal (Janssen et al. 2002) lung maturation. Indeed, the choice of model may be of even greater importance with respect to those mechanisms specifically linked to leptin dynamics, as significant differences in leptin and leptin receptor regulation may exist in pregnancy-associated tissues (fetus, placenta, amniochorion, decidua, etc.) in primates (human and non-human) vs those in nonprimate species (Henson & Castracane 2000, 2002 2003, Bajoria et al. 2002, Sagawa et al. 2002).
With regard to the potential for leptin to modulate pulmonary development and function, cumulative evidence identifies both fetal and adult lungs as leptin-responsive tissues (Chen et al. 1996, Hoggard et al. 1997, Tsuchiya et al. 1999, Dal Farra et al. 2000), and clearly implies roles for the polypeptide in helping to stimulate pulmonary cell proliferation (Tsuchiya et al. 1999) and enhancing stretch-induced surfactant production (Torday & Rehan 2002, Torday et al. 2002, Vlahakis & Hubmayr 2003). In evidence of these effects, genetically obese (ob/ob) mice are unable to produce leptin, but are exposed to leptin in utero by virtue of their propagation in +/+ or ob/+ (leptin-sufficient) dams. However, following birth, lung volume and pulmonary compliance in neonates became attenuated if not supplemented with exogenous leptin (Tankersley et al. 1998). With respect to mice that were leptin receptor deficient due to genetic mutation, Tsuchiya et al. (1999) reported that the rate of tracheal epithelial cell proliferation was only one-quarter (P < 0.01) that of their unaffected littermates, illustrating a potentially important supplementary role for leptin in pulmonary development. Other studies further suggest a significant impact of leptin on general pulmonary health in rodents (O’Donnell et al. 1999), as well as on specific respiratory disorders in humans (O’Donnell et al. 2000). Intriguingly, obesity-related respiratory anomalies are characteristically exacerbated in males (Kapsimalis & Kryger 2002), perhaps reflecting again the gender dichotomy that is typical with respect to circulating leptin concentrations (Casabiell et al. 2001).
In conclusion, we have reported that leptin originating in the placental trophoblast and/or fetal adipose tissue exists in significant concentrations in the circulation of the fetal baboon, attesting to its physiological availability. Although we previously determined that leptin receptor transcripts in both the placental trophoblast and maternal adipose tissues were constitutively expressed throughout baboon pregnancy (Green et al. 2000), our current findings indicate a significant divergence with respect to fetal lung. Thus, transcripts for two isoforms of the leptin receptor were ontogenetically up-regulated in fetal pulmonary tissue with advancing gestation, an effect that was mirrored by the synthesis of leptin receptor protein near term. Immunoblotting of leptin receptor revealed a protein of approximately 130 kDa, similar to that previously reported in other species (Hoggard et al. 1997, Tartaglia 1997, Bergen et al. 2002). Although the determination of a specific cause and effect relationship was beyond the scope of the present study, leptin receptor expression was observed largely in type II epithelial cells, which are responsible for the production of pulmonary surfactant. These constitute the first such observations in a primate. Ontogenetic regulation of the receptor may suggest a role for the polypeptide in modulating general pulmonary development or optimizing surfactant production, and/or may identify leptin receptor as a physiological marker of primate fetal lung maturity.
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Acknowledgements |
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This work was supported by the Department of Obstetrics and Gynecology, and by NIH grant P51 RR00164 and the Tulane National Primate Research Center, Tulane University Health Sciences Center. Presented at the 50th Annual Meeting of the Society for Gynecologic Investigation, March 26–30 2003, Washington, DC, USA.
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Footnotes |
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Received 26 August 2003
First decision 12 September 2003
Accepted 25 September 2003
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 M G Gnanalingham, A Mostyn, D S Gardner, T Stephenson, and M E Symonds Developmental regulation of the lung in preparation for life after birth: hormonal and nutritional manipulation of local glucocorticoid action and uncoupling protein-2. J. Endocrinol., March 1, 2006; 188(3): 375 - 386. [Abstract] [Full Text] [PDF]
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 M. C. Henson and V. D. Castracane Leptin in Pregnancy: An Update Biol Reprod, February 1, 2006; 74(2): 218 - 229. [Abstract] [Full Text] [PDF]
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 M. G. Gnanalingham, A. Mostyn, R. Webb, D. H. Keisler, N. Raver, M. C. Alves-Guerra, C. Pecqueur, B. Miroux, M. E. Symonds, and T. Stephenson Differential effects of leptin administration on the abundance of UCP2 and glucocorticoid action during neonatal development Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1093 - E1100. [Abstract] [Full Text] [PDF]
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