Review Article
The known and unknown of leptin in pregnancy

https://doi.org/10.1016/j.ajog.2005.06.064Get rights and content

Leptin, which was identified originally as an adipocyte-derived protein, was regarded for years as an exclusive regulator of satiety and energy homeostasis. A role for leptin in pregnancy was later suggested by the findings that plasma levels during gestation are greater than in nongravid individuals and that leptin is synthesized within the fetoplacental unit. Observational studies have established that leptin production is dysregulated in several pathologic stages of pregnancy in association with alterations of fetal growth. For example, an overproduction of leptin by the placenta in pregnancy with diabetes mellitus or hypertension is associated with maternal hyperleptinemia. Evidence is also accumulating that umbilical leptin levels can be viewed as a biomarker of fetal adiposity. Ten years after its discovery as a hormone, we review the known and unknowns of leptin in pregnancy with particular emphasis on its functions in health and disease. We aim to demonstrate that studies of leptin in pregnancy largely have contributed to insight into the mechanisms of leptin action, both as a hormone and as a cytokine.

Section snippets

The origin of circulating leptin

Major modifications of circulating leptin levels occur during pregnancy.18, 19 Leptin concentration increases significantly in early pregnancy; it is 30% higher at 12 weeks of gestation compared with pregravid and decreases to pregravid concentrations immediately after delivery (Figure 1). Differences in the gestation-induced leptin rise are noted among species. In the mouse, serum leptin increases 25-fold starting at mid gestation, and the levels are sustained until term.20 In the rat, there

Function of leptin in the mother

Ideally, the pregnant women should maintain a positive energy balance to sustain energy requirements for fetal development; therefore, it is not likely that increased leptin concentrations would affect the individual to reduce her food intake as pregnancy progresses. From a pragmatic point of view, it has to be expected that the rise in maternal leptin level is not accompanied by the classic central effect in the regulation of food intake. However, the increase over pregravid plasma values

References (93)

  • C. Bjorbaek et al.

    SOCS3 mediates feedback inhibition of the leptin receptor via Tyr 985

    J Biol Chem

    (2000)
  • G. Bifulco et al.

    Leptin induces mitogenic effect on human choriocarcinoma cell line (JAr) via MAP kinase activation in a glucose-dependent fashion

    Placenta

    (2003)
  • M. Cauzac et al.

    Transduction of leptin growth signals in placental cells is independent of JAK-STAT activation

    Placenta

    (2003)
  • G. Desoye et al.

    Placental metabolism and its regulation in health and diabetes

    Mol Aspects Med

    (1994)
  • J.F. McCarthy et al.

    Maternal plasma leptin is increased in preeclampsia and positively correlates with fetal cord concentration

    Am J Obstet Gynecol

    (1999)
  • A. Grosfeld et al.

    Hypoxia-inducible factor 1 (HIF-1) transactivates the human leptin gene promoter

    J Biol Chem

    (2002)
  • L.C. Chappell et al.

    A longitudinal study of biochemical variables in women at risk of preeclampsia

    Am J Obstet Gynecol

    (2002)
  • P. Leroy et al.

    Expression of ob gene in adipose cells: regulation by insulin

    J Biol Chem

    (1996)
  • J. Kim et al.

    Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1

    J Clin Invest

    (1998)
  • J. Manderson et al.

    Leptin concentrations in maternal serum and cord blood in diabetic and nondiabetic pregnancy

    Am J Obstet Gynecol

    (2003)
  • O. Langer et al.

    The relationship between large for gestational age infants and glycemic control in women with GDM

    Am Obstet Gynecol

    (1988)
  • P.M. Catalano et al.

    Increased fetal adiposity: a very sensitive marker of abnormal in utero development

    Am J Obstet Gynecol

    (2003)
  • J. Lepercq et al.

    Macrosomia revisited: ponderal index and leptin delineate subtypes of fetal overgrowth

    Am J Obstet Gynecol

    (1999)
  • G. Hervey

    The effects of lesions in the hypothalamus in the parabiotic rats

    J Physiol

    (1958)
  • D. Coleman

    Effects of parabiosis of obese with diabetes and normal mice

    Diabetologia

    (1973)
  • Y. Zhang et al.

    Positional cloning of the mouse ob gene and its human homologue

    Nature

    (1994)
  • M.A. Pelleymounter et al.

    Effects of the obese gene product on body weight regulation in ob/ob mice

    Science

    (1995)
  • V.A. Barr et al.

    Insulin stimulates both leptin secretion and production by rat white adipose tissue

    Endocrinology

    (1997)
  • P. Grasso et al.

    In vivo effects of leptin-related synthetic peptides on body weight and food intake in female ob/ob mice: localization of leptin activity to domains between amino acid residues 106-140

    Endocrinology

    (1997)
  • K.L. Houseknetch et al.

    Evidence of leptin binding in serum of rodents and humans: modulation with obesity

    Diabetes

    (1996)
  • L.A. Campfield et al.

    Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks

    Science

    (1995)
  • J. Friedman et al.

    Leptin and the regulation of body weight in mammals

    Nature

    (1998)
  • M.K. Sinha et al.

    Evidence of free and bound leptin in human circulation: studies in lean and obese subjects during short-term fasting

    J Clin Invest

    (1996)
  • C. Bjorbaek et al.

    Expression of leptin receptor isoforms in rat brain microvessels

    Endocrinology

    (1998)
  • M.W. Schwartz et al.

    Central nervous system control of food intake

    Nature

    (2000)
  • R. Ahima et al.

    Leptin

    Ann Rev Physiol

    (2000)
  • R.B. Harris

    Leptin, much more than a satiety signal

    Ann Rev Nutr

    (2000)
  • M.L. Reitman et al.

    Leptin and its role in pregnancy and fetal development: an overview

    Biochem Soc Trans

    (2001)
  • H. Masuzaki et al.

    Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans

    Nature Med

    (1997)
  • R. Senaris et al.

    Synthesis of leptin in human placenta

    Endocrinology

    (1997)
  • P. Catalano et al.

    Down regulation of IRS-1 and PPARγ in obese women with gestational diabetes: relationship to free fatty acids during pregnancy

    Am J Physiol

    (2002)
  • J. Halaas et al.

    Physiological response to long-term peripheral and central leptin infusion in lean and obese mice

    Proc Natl Acad Sci USA

    (1997)
  • J.W. Sparks et al.

    An estimate of the caloric requirements of the human fetus

    Biol Neonate

    (1980)
  • A. Soukas et al.

    Leptin-specific patterns of gene expression in white adipose tissue

    Gene Dev

    (2000)
  • N. Okereke et al.

    Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance mellitus on cord leptin concentration

    Am J Physiol Endocrinol Metab

    (2004)
  • R. Considine et al.

    Serum immunoreactive leptin concentrations in normal-weight and obese humans

    N Engl J Med

    (1996)

    • Cited by (228)

    • Development, Function, and Pathology of the Placenta

      2023, Avery's Diseases of the Newborn

    • Gene expression of leptin, leptin receptor isoforms and inflammatory cytokines in placentas of obese women – Associations to birth weight and fetal sex

      2022, Placenta

    • Integrated analysis of multiple microarray studies to identify potential pathogenic gene modules in preeclampsia

      2021, Experimental and Molecular Pathology

    • Identification of potential crucial genes associated with early-onset preeclampsia via bioinformatic analysis

      2021, Pregnancy Hypertension
      Citation Excerpt :

      Researchers have found that leptin inhibits increased apoptosis of trophoblasts in PE and suggested that hyperleptinaemia in PE was a compensatory response to increase nutrient delivery to the underperfused placenta [14]. As leptin was a potent angiogenic factor, enhanced placental leptin production could – together with other factors such as vascular endothelial growth factor (VEGF) – increase blood supply to the placenta by neovascularization [14,16–18]. Endoglin as a membrane glycoprotein primarily expressed by the vascular endothelium [19,20], was another candidate serum marker with a high level in serum of its soluble from (sEng) in preeclampsia where it might appear to contribute to endothelial dysfunction by regulating downstream signaling proteins such as BMP4 [21], BMP9 [22], TRIM21 [23] etc.

    • Association of serum and follicular fluid leptin and in vitro Fertilization/ ICSI outcome: A systematic review and meta-analysis

      2021, Journal of Gynecology Obstetrics and Human Reproduction

    • Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis

      2024, International Journal of Molecular Sciences
    View all citing articles on Scopus
    View full text
    Copyright © 2006 Mosby, Inc. All rights reserved.