Leptin is a circulating hormone that is expressed abundantly and specifically in the adipose tissue. It is involved in the regulation of energy homeostasis, as well as the neuroendocrine and reproductive systems. Here, we demonstrate production of leptin by nonadipose tissue, namely, placental trophoblasts and amnion cells from uteri of pregnant women. We show that pregnant women secrete a considerable amount of leptin from the placenta into the maternal circulation as compared with nonpregnant obese women. Leptin production was also detected in a cultured human choriocarcinoma cell line, BeWo cells, and was augmented during the course of forskolin-induced differentiation of cytotrophoblasts into syncytiotrophoblasts. Plasma leptin levels were markedly elevated in patients with hydatidiform mole or choriocarcinoma and were reduced after surgical treatment or chemotherapy. Leptin is also produced by primary cultured human amnion cells and is secreted into the amniotic fluid. The present study provides evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal pregnancy and gestational trophoblastic neoplasms.

Abstract-Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (nϭ458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (nϭ421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, PϽ0.0017; Kumamoto: 0.120 versus 0.058, PϽ0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.(Hypertension. 1998;32:3-8.)Key Words: genes Ⅲ nitric oxide synthase Ⅲ hypertension, essential Ⅲ polymorphism Ⅲ genetics W ith a genetic contribution of from 25% to 60%, human essential hypertension has a genetic basis. Among persons younger than age 50 years, essential hypertension occurs 3.8 times more often in those having two or more first-degree relatives who developed high blood pressure before age 55.1 NO synthesis by the vascular endothelium is important for the regulation of vasodilator tone and the control of blood pressure in humans.2 A recent study using mice with disrupted eNOS gene revealed that eNOS function is required for vascular and hemodynamic responses to acetylcholine and that the disruption of the eNOS gene leads to hypertension. 3 Moreover, recent reports demonstrate that whole-body NO production in patients with essential hypertension is diminished under basal conditions, as established by measurement of urinary and plasma nitrate. 4 In addition, the offspring of hypertensive patients exhibit a reduced response to acetylcholine linked to a defect in the NO pathway.5...

IntroductionObesity is defined as increased mass of adipose tissue and confers a higher risk of arterial blood pressure (BP) elevation or hypertension (1-4). On the other hand, weight reduction lowers BP in obese hypertensive subjects (5-8), suggesting an important association between energy homeostasis and BP. However, the mechanism for that association is poorly understood. Obesity-related hypertension may be secondary to insulin resistance and/or hyperinsulinemia (2,3,8). Several lines of evidence have also suggested that increased sympathetic nerve activity may contribute to the development of obesity-related hypertension (2, 6, 7).The adipose tissue participates in the regulation of a variety of homeostatic processes as an endocrine organ that secretes many biologically active molecules such as FFA, adipsin, angiotensinogen,. Leptin is such an adipocyte-derived hormone that is involved in the regulation of food intake and body weight (10). It also increases the overall sympathetic nerve activity, which leads to a significant increase in energy expenditure (11-15). The biologic actions of leptin are thought to be mediated through the activation of leptin receptor that is expressed in the hypothalamus (16)(17)(18)(19). We and others demonstrated that the hypothalamic arcuate nucleus is a primary site of the satiety effect of leptin (20,21) and that its satiety effect is mediated at least partly by hypothalamic melanocortin system (22,23).Numerous studies have demonstrated that plasma leptin concentrations are elevated significantly in several models of rodent obesity and in human obesity in proportion to the degree of adiposity (24-26), suggesting the state of "leptin resistance" in obesity. Nevertheless, because of the potent pleiotropic actions of leptin, it is conceivable, though paradoxically, that hyperleptinemia may be involved in the pathogenesis of obesity and its related disorders. In this regard, a recent study reported a significant correlation between BP and plasma leptin concentrations in patients with essential hypertension (27), suggesting that leptin may play roles in the pathogenesis of obesity-related hypertension.We have recently produced transgenic skinny mice overexpressing leptin under the control of the liver-specific promoter and demonstrated that chronic hyperleptinemia results in complete disappearance of adipose tissue for a long period (28). These mice also exhibit increased glucose metabolism and insulin sensitivity, accompanied by an activation of insulin signaling in the skeletal muscle and liver (28,29). Accordingly, transgenic skinny mice will serve as the unique experimental model system with which to assess the long-term effects of leptin in vivo. To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA y mice with hyperleptinemia, in which hypothalamic melano...

Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts that correlates with impaired cardiac function and poor prognosis. However, the mechanism governing the reversible expression of fetal cardiac genes remains unresolved. Here we show that neuronrestrictive silencer factor (NRSF), a transcriptional repressor, selectively regulates expression of multiple fetal cardiac genes, including those for atrial natriuretic peptide, brain natriuretic peptide and a-skeletal actin, and plays a role in molecular pathways leading to the re-expression of those genes in ventricular myocytes. Moreover, transgenic mice expressing a dominant-negative mutant of NRSF in their hearts exhibit dilated cardiomyopathy, high susceptibility to arrhythmias and sudden death. We demonstrate that genes encoding two ion channels that carry the fetal cardiac currents I f and I Ca,T , which are induced in these mice and are potentially responsible for both the cardiac dysfunction and the arrhythmogenesis, are regulated by NRSF. Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function.

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