Leptin in Relation to Growth and Developmental Processes in the Fetus

Helen Christou; Shanti Serdy; Christos S. Mantzoros

doi:10.1055/s-2002-32503

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2002; 20(2): 123-130
DOI: 10.1055/s-2002-32503

Leptin in Relation to Growth and Developmental Processes in the Fetus

Helen Christou¹ , Shanti Serdy² , Christos S. Mantzoros²

¹Division of Newborn Medicine, Children's Hospital
²Division of Endocrinology, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Abstract

ABSTRACT

Leptin, a 16-kilodalton protein secreted by the adipose tissue in proportion to the amount of energy stored in adipose tissue, conveys to the hypothalamus information on energy homeostasis and regulates reproductive function. In addition, there is accumulating evidence that leptin produced by placental or fetal tissues acts through specific leptin receptors to regulate fetal growth and development. Although leptin levels are correlated with insulin and insulin-like growth factor (IGF)-1 levels, observational studies in humans indicate that its effects on fetal growth are independent of these axes and of adiposity. The extent to which leptin per se mediates the fetal growth and developmental abnormalities associated with disease states such as diabetes, hypoxia, or preeclampsia remains to be fully clarified by future studies in humans. It is hoped that clarification of these mechanisms may provide novel therapeutic approaches.

KEYWORDS

Leptin - fetus - growth

Full Text

References

REFERENCES

1 Holness M J, Munns M J, Sugden M C. Current concepts concerning the role of leptin in reproductive function. Mol Cell Endocrinol . 1999; 157 11-20
2 Chehab F F, Lim M E, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet . 1996; 12 318-320
3 Mounzih K, Lu R, Chehab F F. Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology . 1997; 138 1190-1193
4 Mantzoros C S. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med . 1999; 130 671-680
5 Strobel A, Issad T, Camoin L, Ozata M, Strosberg A D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet . 1998; 18 213-215
6 Masuzaki H, Ogawa Y, Sagawa N. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med . 1997; 3 1029-1033
7 Ashworth C J, Hoggard N, Thomas L, Mercer J G, Wallace J M, Lea R G. Placental leptin. Rev Reprod . 2000; 5 18-24
8 Hoggard N, Hunter L, Duncan J S, Williams L M, Trayhurn P, Mercer J G. Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc Natl Acad Sci U S A . 1997; 94 11073-11078
9 Hoggard N, Haggarty P, Thomas L, Lea R G. Leptin expression in placental and fetal tissues: does leptin have a functional role?. Biochem Soc Trans . 2001; 29 57-63
10 Islam M S, Sjoholm A, Emilsson V. Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells. Int J Obes Relat Metab Disord . 2000; 24 1246-1253
11 Lepercq J, Challier J C, Guerre-Millo M, Cauzac M, Vidal H, Hauguel-de Mouzon S. Prenatal leptin production: evidence that fetal adipose tissue produces leptin. J Clin Endocrinol Metab . 2001; 86 2409-2413
12 Marti A, Berraondo B, Martinez J A. Leptin: physiological actions. J Physiol Biochem . 1999; 55 43-49
13 Wang Y, Kuropatwinski K K, White D W. Leptin receptor action in hepatic cells. J Biol Chem . 1997; 272 16216-16223
14 Reitman M L, Bi S, Marcus-Samuels B, Gavrilova O. Leptin and its role in pregnancy and fetal development: an overview. Biochem Soc Trans . 2001; 29 68-72
15 Moschos S, Chan J L, Mantzoros C S. Leptin and reproduction: a review. Fertil Steril . 2002; 77 433-444
16 Licinio J, Negrao A B, Mantzoros C. Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women. Proc Natl Acad Sci U S A . 1998; 95 2541-2546
17 Sir-Petermann T, Recabarren S E, Lobos A, Maliqueo M, Wildt L. Secretory pattern of leptin and LH during lactational amenorrhoea in breastfeeding normal and polycystic ovarian syndrome women. Hum Reprod . 2001; 16 244-249
18 Sir-Petermann T, Maliqueo M, Palomino A, Vantman D, Recabarren S E, Wildt L. Episodic leptin release is independent of luteinizing hormone secretion. Hum Reprod . 1999; 14 2695-2699
19 Farooqi I S, Jebb S A, Langmack G. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med . 1999; 341 879-884
20 Sivan E, Whittaker P G, Sinha D. Leptin in human pregnancy: the relationship with gestational hormones. Am J Obstet Gynecol . 1998; 179 1128-1132
21 Lea R G, Howe D, Hannah L T, Bonneau O, Hunter L, Hoggard N. Placental leptin in normal, diabetic and fetal growth-retarded pregnancies. Mol Hum Reprod . 2000; 6 763-769
22 Lepercq J, Cauzac M, Lahlou N. Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes . 1998; 47 847-850
23 Mise H, Sagawa N, Matsumoto T. Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia. J Clin Endocrinol Metab . 1998; 83 3225-3229
24 McCarthy J F, Misra D N, Roberts J M. Maternal plasma leptin is increased in preeclampsia and positively correlates with fetal cord concentration. Am J Obstet Gynecol . 1999; 180 731-736
25 Antczak M, Van Blerkom J, Clark A. A novel mechanism of vascular endothelial growth factor, leptin and transforming growth factor-beta2 sequestration in a subpopulation of human ovarian follicle cells. Hum Reprod . 1997; 12 2226-2234
26 Matsuoka T, Tahara M, Yokoi T. Tyrosine phosphorylation of STAT3 by leptin through leptin receptor in mouse metaphase 2 stage oocyte. Biochem Biophys Res Commun . 1999; 256 480-484
27 Takeda K, Noguchi K, Shi W. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A . 1997; 94 3801-3804
28 Mounzih K, Qiu J, Ewart-Toland A, Chehab F F. Leptin is not necessary for gestation and parturition but regulates maternal nutrition via a leptin resistance state. Endocrinology . 1998; 139 5259-5262
29 Gonzalez R R, Caballero-Campo P, Jasper M. Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J Clin Endocrinol Metab . 2000; 85 4883-4888
30 Chardonnens D, Cameo P, Aubert M L. Modulation of human cytotrophoblastic leptin secretion by interleukin-1alpha and 17beta-oestradiol and its effect on HCG secretion. Mol Hum Reprod . 1999; 5 1077-1082
31 Simon C, Polan M L. Cytokines and reproduction. West J Med . 1994; 160 425-429
32 Wolf H J, Ebenbichler C F, Huter O. Fetal leptin and insulin levels only correlate in large-for-gestational age infants. Eur J Endocrinol . 2000; 142 623-629
33 Mantzoros C S, Cramer D W, Liberman R F, Barbieri R L. Predictive value of serum and follicular fluid leptin concentrations during assisted reproductive cycles in normal women and in women with the polycystic ovarian syndrome. Hum Reprod . 2000; 15 539-544
34 Tomimatsu T, Yamaguchi M, Murakami T. Increase of mouse leptin production by adipose tissue after midpregnancy: gestational profile of serum leptin concentration. Biochem Biophys Res Commun . 1997; 240 213-215
35 Kawai M, Yamaguchi M, Murakami T, Shima K, Murata Y, Kishi K. The placenta is not the main source of leptin production in pregnant rat: gestational profile of leptin in plasma and adipose tissues. Biochem Biophys Res Commun . 1997; 240 798-802
36 Gavrilova O, Barr V, Marcus-Samuels B, Reitman M. Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor. J Biol Chem . 1997; 272 30546-30551
37 Varvarigou A, Mantzoros C S, Beratis N G. Cord blood leptin concentrations in relation to intrauterine growth. Clin Endocrinol (Oxf) . 1999; 50 177-183
38 Mantzoros C S, Varvarigou A, Kaklamani V G, Beratis N G, Flier J S. Effect of birth weight and maternal smoking on cord blood leptin concentrations of full-term and preterm newborns. J Clin Endocrinol Metab . 1997; 82 2856-2861
39 Christou H, Connors J M, Ziotopoulou M. Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth. J Clin Endocrinol Metab . 2001; 86 935-938
40 Harigaya A, Nagashima K, Nako Y, Morikawa A. Relationship between concentration of serum leptin and fetal growth. J Clin Endocrinol Metab . 1997; 82 3281-3284
41 Ong K K, Ahmed M L, Sherriff A. Cord blood leptin is associated with size at birth and predicts infancy weight gain in humans. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. J Clin Endocrinol Metab . 1999; 84 1145-1148
42 Koistinen H A, Koivisto V A, Andersson S. Leptin concentration in cord blood correlates with intrauterine growth. J Clin Endocrinol Metab . 1997; 82 3328-3330
43 Coutant R, Boux de Casson F, Douay O. Relationships between placental GH concentration and maternal smoking, newborn gender, and maternal leptin: possible implications for birth weight. J Clin Endocrinol Metab . 2001; 86 4854-4859
44 Kolaczynski J W, Nyce M R, Considine R V. Acute and chronic effects of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes . 1996; 45 699-701
45 Islam M S, Morton N M, Hansson A, Emilsson V. Rat insulinoma-derived pancreatic beta-cells express a functional leptin receptor that mediates a proliferative response. Biochem Biophys Res Commun . 1997; 238 851-855
46 Yamashita H, Shao J, Ishizuka T. Leptin administration prevents spontaneous gestational diabetes in heterozygous Lepr(db/+) mice: effects on placental leptin and fetal growth. Endocrinology . 2001; 142 2888-2897
47 Clement K, Vaisse C, Lahlou N. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature . 1998; 392 398-401
48 Bouloumie A, Drexler H C, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ Res . 1998; 83 1059-1066
49 Sierra-Honigmann M R, Nath A K, Murakami C. Biological action of leptin as an angiogenic factor. Science . 1998; 281 1683-1686
50 Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci . 2001; 47 141-150
51 Gainsford T, Willson T A, Metcalf D. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A . 1996; 93 14564-14568
52 Umemoto Y, Tsuji K, Yang F C. Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells. Blood . 1997; 90 3438-3443
53 Loffreda S, Yang S Q, Lin H Z. Leptin regulates proinflammatory immune responses. FASEB J . 1998; 12 57-65
54 Lord G M, Matarese G, Howard J K, Baker R J, Bloom S R, Lechler R I. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature . 1998; 394 897-901
55 Ozata M, Ozdemir I C, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab . 1999; 84 3686-3795
56 Figenschau Y, Knutsen G, Shahazeydi S, Johansen O, Sveinbjornsson B. Human articular chondrocytes express functional leptin receptors. Biochem Biophys Res Commun . 2001; 287 190-197
57 Ogueh O, Sooranna S, Nicolaides K H, Johnson M R. The relationship between leptin concentration and bone metabolism in the human fetus. J Clin Endocrinol Metab . 2000; 85 1997-1999
58 Matkovic V, Ilich J Z, Skugor M. Leptin is inversely related to age at menarche in human females. J Clin Endocrinol Metab . 1997; 82 3239-3245
59 Gurgol C M, Roemmich J N, Clark P A, Mantzoros C S, Weltman A, Rogol A D. Serum leptin concentrations are related to bone mass in youth (in press). Endocr Soc Abs . 2002;
60 Thomas T, Gori F, Khosla S, Jensen M D, Burguera B, Riggs B L. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology . 1999; 140 1630-1638
61 Ducy P, Amling M, Takeda S. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell . 2000; 100 197-207
62 Rossier J, Rogers J, Shibasaki T, Guillemin R, Bloom F E. Opioid peptides and alpha-melanocyte-stimulating hormone in genetically obese (ob/ob) mice during development. Proc Natl Acad Sci U S A . 1979; 76 2077-2080
63 Bereiter D A, Jeanrenaud B. Altered neuroanatomical organization in the central nervous system of the genetically obese (ob/ob) mouse. Brain Res . 1979; 165 249-260
64 Bereiter D A, Jeanrenaud B. Altered dendritic orientation of hypothalamic neurons from genetically obese (ob/ob) mice. Brain Res . 1980; 202 201-206
65 Sena A, Sarlieve L L, Rebel G. Brain myelin of genetically obese mice. J Neurol Sci . 1985; 68 233-243
66 Ahima R S, Bjorbaek C, Osei S, Flier J S. Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology . 1999; 140 2755-2762