子宮内環境と胎児(特別講演,第62回日本産科婦人科学会・学術講演会) Intrauterine Milieu and Fetus
Fetal life entirely depends on oxygen and nutrient supply from mother through the placenta, which is the most important constituent of intrauterine milieu. On the other hand, fetus and its accessories produce and secrete various bioactive substances, and contribute formation or modulation of the intrauterine milieu, which regulates fetal growth as well as initiation of parturition. Thus, formation of adequate intrauterine milieu is necessary for normal fetal development and conversely, physical and biochemical signals released from the developed fetus initiate parturition and remove the fetus from intrauterine milieu by terminating pregnancy (delivery). Cyclic mechanical stretch enhances phospholipase A_2 expression and prostaglandin production in the lower uterine segment and adjacent fetal membranes. Matrix metalloproteinase-1 (MMP-1) and elastase are believed to play an important role in the degradation of extracellular matrix of the uterine cervix during parturition. Leukocyte infiltration into the cervix is a characteristic feature of parturition. The mRNA expression and protein secretion of both interleukin-8 (IL-8) and monocyte chemotactic protein-3 (MCP-3) in the cultured human uterine cervical fibroblast cells significantly increased after stimulation with cyclic mechanical stretch. In conclusion, cyclic mechanical stretch by presenting part of the developed fetus at term may initiate or facilitate cervical ripening through augmentation of production of IL-8 and MCP-3 followed by infiltration of neutrophils and monocytes/macrophages and increased secretion of MMP-1 and elastase in the uterine cervix, thus finally result in the initiation of labor and delivery of the fetus. Dramatic changes in energy metabolism are well recognized in pregnant women. Increased food intake, decreased insulin sensitivity and hyperlipidemia are major features during pregnancy. These changes are beneficial in providing energy to the fetus and preparing the mother for nursing. It is proposed that maternal adaptation to the pregnant state is mainly due to placental hormones, such as prolactin, placental lactogen and steroid hormones. Leptin was initially introduced as an adipocyte-derived messenger of energy metabolism. Subsequently, we revealed that leptin is produced in the human placenta and is secreted into both maternal and fetal circulation. Since leptin receptor is abundantly expressed in various maternal tissues, placenta and fetal tissues, physiological and pathophysiological roles in pregnancy are expected. Resistin is another adipocyte-derived peptide hormone that regulates insulin resistance and development of type II diabetes mellitus. We found that rersistin is expressed in the human placenta, and the expression in this tissue is higher than that in adipose tissue. Thus, it is plausible that placentaderived resistin may have physiological significance in the regulation of maternal glucose metabolism by decreasing insulin sensitivity during human pregnancy. In summary, the present study provides the evidence for leptin as a novel placenta-derived hormone in humans, and suggests the physiologic and pathophysiologic significance of leptin in fetal growth in normal and complicated pregnancy. Moreover, we have demonstrated for the first time that the resistin gene is expressed in the human placental tissue, leading to a novel view of resistin as a placenta-derived regulator of glucose metabolism during pregnancy. However, interaction between leptin and resistin actions has not been studied. Further investigation on the effects of both leptin and resistin on the maternal glucose metabolism and insulin sensitivity may provide better understanding of the placental role in the maternal energy metabolism and fetal growth. A number of epidemiological human studies and experimental animal studies revealed that offspring born small for gestational age from undernourished mother develop various adult diseases including obesity, diabetes, hypertension and cardiovascular disease in their later life. Such a process is named as to fetal programming. Adipocytokines, such as leptin, adiponectin, resistin, TNFα are involved in the development of obesity-related metabolic disorders. To elucidate the role of adipose tissue in the fetal programming, we examined the expressions of adipocytokines in the fetal adipose tissue using mice model under various nutritional conditions. Mice offspring from undernourished mother are born as IUGR and exhibit pronounced obesity on a high fat diet (HFD) in their later life. Expressions of leptin, resistin and adiponectin in the subcutaneous adipose tissue of IUGR mice fetuses produced by maternal food restriction were all significantly suppressed as compared to those in the fetuses from normal nourished mother (control). However, at 8 days of age, expression of leptin, but not adiponectin or resistin was enhanced as compared to control offspring. When leptin was administered to normal nourished offspring at catch-up period (5 to 10 days of delivery), these offspring developed obesity when they were exposed to HFD, suggesting that this premature rise in plasma leptin concentration in the IUGR fetus is critically involved in the development of obesity in their later life. Thus, the changes in the adiocytokines in the fetal adipose tissue may be the key to understand pathophysiology of development of obesity in IUGR fetus in their later life. To further understand the regulatory mechanism of adipocytokine expression in the adipose tissue during perinatal period, we examined the effects of maternal HFD on adipocytokine expression in the fetal adipose tissue using HFD-induced obese pregnant mice. HFD-induced obese pregnant mice showed impaired glucose tolerance as compared to normal chow diet (NCD) group. On day 17 of pregnancy, dams were sacrificed and fetal blood and subcutaneous adipose tissue were removed for experimental use. Although fetal blood glucose and plasma insulin levels were higher in the HFD group than those in the NCD group, fetal weights were not different between two groups. Adipocytes in the fetal adipose tissue of HFD group were hypertrophic as compared with those of NCD group. In adipose tissue, TNFα and leptin mRNA levels were higher but GLUT-4 mRNA levels were lower in the HFD group than those in the NCD group. These results suggest that fetuses exposed to maternal HFD during pregnancy develop insulin-resistance even in the uterus. The mechanism may be related to the decreased GLUT-4 mRNA levels of fetal adipose tissue through the alterations of gene expression of adipocytokines. These findings suggest a possibility that not only undernutrition but also high fat diet during pregnancy affect adipocytokine expression in the fetal adipose tissue and finally modulate energy metabolism in their later life.