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Obstetrics & Gynecology 2002;100:655-658
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Leptin as an Acute Stress-Related Hormone in the Fetoplacental Circulation

Yuichiro Takahashi, MD, PhD, Yasuhiro Yokoyama, MD, PhD, Ichiro Kawabata, MD, PhD, Shinichi Iwasa, MD, PhD and Teruhiko Tamaya, MD, PhD

From the Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu City, Japan; and Department of Obstetrics and Gynecology, Iwasa Hospital, Gifu City, Japan.

Address reprint requests to: Yuichiro Takahashi, MD, PhD, Gifu University School of Medicine, Department of Obstetrics and Gynecology, Tsukasamachi-40, Gifu City, 500-8705, Japan; E-mail: y-taka{at}cc.gifu-u.ac.jp.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To investigate the relationship between fetoplacental leptin secretion and blood gases.

METHODS: We measured the levels of umbilical arterial and venous leptin, umbilical cord gas, umbilical venous blood glucose, and estradiol-17ß (E2) in 89 pregnant women. Correlation between the leptin levels and other variables (gestational age, birth weight, maternal body weight, height, body mass index, maternal body weight gain, placental weight, umbilical cord gas data, and levels of umbilical venous blood glucose and E2) were examined statistically.

RESULTS: Umbilical arterial and venous leptin levels were 7.64 ± 12.76 and 7.76 ± 13.17 (ng/mL), respectively, correlating positively with carbon dioxide pressure levels (r = 0.446, P < .001; r = 0.406, P < .001, respectively) and correlating inversely with pH (r = -0.337, P =.001; r = -0.247, P = .019, respectively). Umbilical venous glucose, E2, and other factors did not correlate with leptin levels.

CONCLUSION: Leptin secretion into the fetoplacental circulation may be associated with fetal hypercapnia, suggesting two important roles for leptin: one for basal control of fetal fat tissue and one as an acute stress-related hormone.

Leptin is a 16-kD protein encoded by the ob gene. It is a hormone secreted by adipocytes1 and acts on the hypothalamic centers to regulate body weight,2 causing a decrease in food intake and an increase in body temperature and energy expenditure.3,4 In 1997, Masuzaki et al demonstrated leptin production in nonadipose tissues such as human placental trophoblastic and amniotic cells and in gestational trophoblastic neoplasms.5 The biological implication of circulated fetoplacental leptin is still controversial. Birth weight and placental weight positively correlated with umbilical cord blood leptin level,6–9 which has an independent association with intrauterine growth restriction10,11 and macrosomia.12 Maternal serum leptin was drastically reduced after placenta delivery,5 yet there was no correlation between maternal and cord leptin levels.13 This evidence shows that leptin’s fetoplacental circulation is independent of its maternal circulation. The release of leptin from placenta into the fetal circulation was very low, compared with the release into the maternal circulation.14 Fetoplacental circulation of leptin may be influenced not only by fetal growth and fat tissue, but also by other related systems.

In adult humans, leptin is discussed as a stress-related hormone.15–18 Chronic or repeated stress results in reduction of food intake and body weight in rats,19 suggesting that leptin plays a bridging role between stress and body fat control for maintaining homeostasis and energy supply. The aim of the present study is to clarify a plausible relationship between fetal distress and leptin secretion in fetoplacental circulation. Our hypothesis was that leptin may be not only a growth-related hormone but also a bridging hormone between fetal stress and fetal energy control (fetal fat tissue decrease and fetal growth restriction).


   MATERIALS AND METHODS
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ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eighty-nine randomly selected pregnant women (Table 1Go) were enrolled in the study at the Department of Obstetrics and Gynecology, Gifu University School of Medicine, between January 1999 and June 2000. Prior informed, written consent for the following study was obtained from the women and the Research Committee for Human Subjects. Gestational age was 34–41 weeks. There were four fetuses with growth restriction and two with macrosomia, along with four women with preeclampsia and three women with diabetes mellitus.


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  		Table 1. Clinical Data of 89 Cases
 
Umbilical arterial (UA) and venous (UV) blood was collected at birth. All serum samples were stored at -20C until assayed. Serum leptin levels were measured by radioimmunoassay (Linco Research, St. Charles, MO) as previously described.20 Blood gas analysis was performed using a RADIOMETER analyzer (RADIOMETER, Copenhagen, Denmark). The UV blood glucose and estradiol-17ß (E2) levels were measured by routine methods for evaluation of maternal hyperglycemia21 and hormonal factors,22 respectively.

The paired Student t test for analysis of UA and UV leptin level differences was performed, and multivariate analysis between leptin levels and other variables—gestational age, birth weight, maternal body weight, maternal body weight gain, maternal height, maternal body mass index, placental weight, UV blood glucose, UV E2, UA and UV pH, oxygen pressure, carbon dioxide pressure, and base excess (Tables 1Go and 2Go) was performed. A P value of <.05 was considered significant. We evaluated the fetal stress using the umbilical cord gas analysis after birth.


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  		Table 2. Umbilical Artery and Vein Leptin Levels With Other Parameters
 

   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The UA and UV leptin levels were 7.64 ± 12.76 and 7.76 ± 13.17 (ng/mL), respectively (Table 2Go), and there was no significant difference between them by the paired Student t test. The UA and UV levels positively correlated with carbon dioxide pressure (r = 0.446, P < .001; r = 0.406, P < .001, respectively) (Figure 1Go) and inversely correlated with pH (r = -0.337, P = .001; r = -0.247, P = .019, respectively) (Table 3Go). There was no correlation between leptin levels and oxygen pressure, nor between leptin levels and base excess of UA and UV.



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  		Figure 1. Correlation between umbilical arterial (UA) leptin levels and carbon dioxide pressure (PCO2).

Takahashi. Leptin and Fetal Stress. Obstet Gynecol 2002.

 

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  		Table 3. Correlation of Umbilical Artery Blood Gas Parameters and Leptin Levels
 
All maternal factors, UV blood glucose, and E2 failed to correlate with UA and UV leptin levels. Though the number of data is small, umbilical cord leptin has no tendency in each high-risk groups (growth-restricted fetus, macrosomia, maternal preeclampsia, maternal diabetes mellitus) (Figure 2Go).



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  		Figure 2. Umbilical arterial leptin levels classified by the cases of fetal growth restrictions (A), macrosomia (B), maternal preeclampsia (C), maternal diabetic mellitus (D), and normal pregnancy (E). *Average value of umbilical arterial leptin concentration: 7.64 ± 12.76 (ng/mL) (see Table 2Go). **Severe fetal distress with diabetic mother.

Takahashi. Leptin and Fetal Stress. Obstet Gynecol 2002.

 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Hypercapnia of the umbilical cord, monitored as fetal distress, is induced by acute placental dysfunction and umbilical cord occlusion. In this study, hypercapnia, but not base excess, correlated with leptin level, suggesting that leptin may be associated with acute stress. In adult humans, a significant correlation was reported between baseline levels of leptin and body mass index 3 days before cholecystectomy, but on the third postoperative day, there were significant increases in the serum levels of cortisol, free fatty acids, leptin, and C-reactive protein,18 suggesting that there may be two biological implications of leptin secretion in body mass index and surgical stress. In the fetoplacental circulation, respiratory acidosis, which is one stress-related factor, may induce leptin secretion. Umbilical cord erythropoietin as an adaptation factor for hypoxia is also associated with cord blood leptin in mothers with insulin-dependent diabetes mellitus.21 Intrauterine growth restriction infants show an increased leptin level in the umbilical cord,11 whereas there is a positive correlation between fetal leptin levels and fetal fat mass in severe intrauterine growth restriction,23 demonstrating conflicting roles for leptin secretion from fetal fat mass. Intrauterine growth restriction induces chronic and acute asphyxic conditions via the stress of labor (contraction stress), causing an alteration in umbilical cord leptin levels.

Leptin secretion is increased in a human trophoblastic carcinoma cell line (BeWo cells) under hypoxic conditions, compared with those under normal conditions.24 The experiment may indicate that additional leptin secretion in the fetoplacental circulation has some relation with fetal asphyxia, but the evidence supported by that report is at present insufficient.

Cord blood hypertriglyceridemia is important for fetal energy supply when the fetus becomes asphyxic.25 Fetal hypoxia induces hypersecretion of catecholamines from fetal adrenal glands and accelerates the energy production of blood glucose from glycogen. When a fetus undergoes stress, free fatty acid may be secreted as a second energy source to compensate for increased glucose consumption, and leptin may have some relation with this mechanism. These metabolic features may have some connection to fetoplacental leptin secretion.

In conclusion, although the pathophysiology of leptin secretion in the fetoplacental circulation is complicated and leptin secretion seemingly has contradictory functions, it seems likely that leptin may have two important roles: one as an acute stress-related hormone, and the other for fetal fat mass control. Further investigation into these theories could possibly clarify some mechanisms of fetal growth restriction and fetal asphyxia.


   Footnotes
 
The authors express their gratitude to Mr. John Cole for reading our draft and giving us suggestions on language and style.

PII S0029-7844(02)02159-2

Received September 10, 2001. Received in revised form March 29, 2002. Accepted April 18, 2002.


   REFERENCES
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ABSTRACT
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 RESULTS
 DISCUSSION
 REFERENCES
 
1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32.[Medline]

2. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292–5.[Abstract/Free Full Text]

3. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540–3.[Abstract/Free Full Text]

4. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269: 543–6.[Abstract/Free Full Text]

5. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, et al. Nonadipose tissue production of leptin: Leptin as a novel placenta-derived hormone in humans. Nat Med 1997;3:1029–33.[Medline]

6. Schubring C, Kiess W, Englaro P, Rascher W, Dotsch J, Hanitsch S, et al. Levels of leptin in maternal serum, amniotic fluid, and arterial and venous cord blood: Relation to neonatal and placental weight. J Clin Endocrinol Metab 1997;82:1480–3.[Abstract/Free Full Text]

7. Geary M, Pringle PJ, Persaud M, Wilshin J, Hindmarsh PC, Rodeck CH, et al. Leptin concentrations in maternal serum and cord blood: Relationship to maternal anthropometry and fetal growth. Br J Obstet Gynaecol 1999;106: 1054–60.[Medline]

8. Jaquet D, Leger J, Levy-Marchal C, Oury JF, Czernichow P. Ontogeny of leptin in human fetuses and newborns: Effect of intrauterine growth retardation on serum leptin concentrations. J Clin Endocrinol Metab 1998;83:1243–6.[Abstract/Free Full Text]

9. Cetin I, Morpurgo PS, Radaelli T, Taricco E, Cortelazzi D, Bellotti M, et al. Fetal plasma leptin concentrations: Relationship with different intrauterine growth patterns from 19 weeks to term. Pediatr Res 2000;48:646–51.[Medline]

10. Varvarigou A, Mantzoros CS, Beratis NG. Cord blood leptin concentrations in relation to intrauterine growth. Clin Endocrinol (Oxf) 1999;50:177–83.[Medline]

11. Shekhawat PS, Garland JS, Shivpuri C, Mick GJ, Sasidharan P, Pelz CJ, et al. Neonatal cord blood leptin: Its relationship to birth weight, body mass index, maternal diabetes, and steroids. Pediatr Res 1998;43:338–43.[Medline]

12. Wiznitzer A, Furman B, Zuili I, Shany S, Reece EA, Mazor M. Cord leptin level and fetal macrosomia. Obstet Gynecol 2000;96:707–13.[Abstract/Free Full Text]

13. Laml T, Hartmann BW, Ruecklinger E, Preyer O, Soeregi G, Wagenbichler P. Maternal serum leptin concentrations do not correlate with cord blood leptin concentrations in normal pregnancy. J Soc Gynecol Invest 2001;8:43–7.[Medline]

14. Linnemann K, Malek A, Sager R, Blum WF, Schneider H, Fusch C. Leptin production and release in the dually in vitro perfused human placenta. J Clin Endocrinol Metab 2000;85:4298–301.[Abstract/Free Full Text]

15. Bornstein SR. Is leptin a stress related peptide? Nat Med 1997;3:937.[Medline]

16. Hernandez C, Simo R, Chacon P, Sabin P, Baena JA, Castellanos JM, et al. Influence of surgical stress and parenteral nutrition on serum leptin concentration. Clin Nutr 2000;19:61–4.[Medline]

17. Pickup JC, Chusney GD, Mattock MB. The innate immune response and type 2 diabetes: Evidence that leptin is associated with a stress-related (acute-phase) reaction. Clin Endocrinol 2000;52:107–12.[Medline]

18. Wallace AM, Sattar N, McMillan DC. The co-ordinated cytokine/hormone response to acute injury incorporates leptin. Cytokine 2000;12:1042–5.[Medline]

19. Makino S, Asaba K, Nishiyama M, Hashimoto K. Decreased type 2 corticotropin-releasing hormone receptor mRNA expression in the ventromedial hypothalamus during repeated immobilization stress. Neuroendocrinology 1999;70:160–7.[Medline]

20. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155–61.[Medline]

21. Gross GA, Solenberger T, Philpott T, Holcomb WL Jr, Landt M. Plasma leptin concentrations in newborns of diabetic and nondiabetic mothers. Am J Perinatol 1998;15: 243–7.[Medline]

22. Kitawaki J, Kusuki I, Koshiba H, Tsukamoto K, Honjo H. Leptin directly stimulates aromatase activity in human luteinized granulosa cells. Molec Hum Reprod 1999;5: 708–13.[Abstract/Free Full Text]

23. Hytinantti TK, Koistinen HA, Teramo K, Karonen SL, Koivisto VA, Andersson S. Increased fetal leptin in type I diabetes mellitus pregnancies complicated by chronic hypoxia. Diabetologia 2000;43:709–13.[Medline]

24. Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H, et al. Augmented placental production of leptin in preeclampsia: Possible involvement of placental hypoxia. J Clin Endocrinol Metab 1998;83:3225–9.[Abstract/Free Full Text]

25. Andersen GE, Friis-Hansen B. Neonatal hypertriglyceridemia: A new index of antepartum-intrapartum fetal stress? Acta Paediatr Scand 1976;65:369–74.[Medline]




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