1998 Fiscal Year Final Research Report Summary
Study on the Role of Obese Gene Product, Leptin in the Regulation of Reproduction and Maintenance of Pregnancy
| Project/Area Number |
09671675
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
FUKUOKA Masatsune Kyoto University Graduate School of Medicine, Lecturer, 医学研究科, 講師 (80243012)
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| Co-Investigator(Kenkyū-buntansha) |
SAGAWA Norimasa Kyoto University Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (00162321)
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| Project Period (FY) |
1997 – 1998
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| Keywords | leptin / ovary / puberty / placenta / pregnancy / reproduction / transgenic mice / trophoblast |
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| Research Abstract |
Leptin is a novel hormone that is expressed abundantly and specifically in the adipose tissue. It decreases food intake and body weight via its cognate receptor (Ob-R) in the hypothalamus. It acts also as a peripherally-produced metabolic signal to the neuro-endocrine and reproductive systems.
In the present study, we demonstrated non-adipose tissue production of leptin. Leptin is produced by placental trophoblasts and amnion cells from human pregnant uteri. In pregnant women, leptin was secreted from the placenta into the maternal circulation at a considerable amount comparable to those in non-pregnant obese women. Leptin was also present in feto-placental circulation. Higher leptin levels in umbilical veins than in umbilical arteries and marked decrease during neonatal period suggest that the placenta is one of the major sources of leptin in fetal circulation. We also examined immunohistochemical localization of leptin and obese gene expression in molar tissues in 7 women with hydatid
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iform mole. Immunohistochemically, trophoblast cells were clearly stained for leptin. Northern blot analysis demonstrated augmented obese gene expression in molar tissue. Plasma leptin levels in patients with hydatidiform mole were 2-fold higher than those in age- and BMI-matched normal pregnant women in the first trimester. These findings indicate that hydatidiform mole is a leptin-producing tumor.
We have also revealed that leptin gene expression in placenta was augmented in severe preeclampsia, and suggested that placental hypoxia may play a role in this augmented gene expression. On the other hand, leptin gene expression in the human choriocarcinoma cell line (BeWo cells) and in organ culture of human olacental chorionic tissue were increased by forskolin (FK) and phorbol myristate acetate (PMA). Such stimulations by EK and PMA were completely blocked by H89 and H7, respectively, suggesting that leptin secretion in the trophoblast cells is regulated by both protein kinase A and C.However, the involvement of PKA and PKC in the augmentation of leptin gene expression in the placenta of severe preeclampsia must be the purpose of future investigation.
The present study provides the first evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal and abnormal pregnancy.
Leptin acts also as a peripherally-produced metabolic signal to the neuro-endocrine and reproductive systems. In this study, we generated transgenic mice overexpressing leptin in order to determine whether the hyper-leptinemia alters the onset of sexual maturation and maintenance of reproductive functions in transgenic mice. Overexpression of leptin has reduced body weight of Tg to approximately 70% of those observed in non-Tg. Adipose tissue was completely missing both visually and histologically in Tg, which we called transgenic skinny mice. Although transgenic skinny mice overexpressing leptin lost adipose tissue completely, sexual maturation occurred earlier and reproductive functions remained active in these mice.
These findings suggest that leptin is a major mediator of fat cell-derived signals that regulate the onset of puberty and the maintenance of reproductive functions. Less
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