Maternal glucocorticoid treatment modulates placental leptin and leptin receptor expression and materno-fetal leptin physiology during late pregnancy, and elicits hypertension associated with hyperleptinaemia in the early-growth-retarded adult offspring

Background: Leptin concentrations are increased during late pregnancy, and leptin receptors are expressed in placental and fetal tissues, suggesting a role for leptin in placental and/or fetal growth, or both. In humans, lept in concentrations in adulthood are inversely related to body weight at birt h, independent of adult adiposity, and correlate with fasting insulin. Gluc ocorticoids and insulin regulate leptin secretion. Excessive exposure to gl ucocorticoids during late fetal development in the rat causes intrauterine growth retardation (IUGR), together with hypertension and hyperinsulinaemia in adulthood. Leptin may have a role in the development of some forms of h ypertension. Objective: To determine whether IUGR induced by maternal glucocorticoid tre atment during the last third of pregnancy in the rat is associated with mod ulation of either maternal or fetal leptin concentrations, the placental ex pression of leptin or the short form of the leptin receptor (ObR-S). or com binations thereof, and to evaluate whether hypertension or hyperinsulinaemi a in the early-growth-retarded adult progeny of dexamethasone-treated dams is associated with altered leptin concentrations. Design and Methods: Dexamethasone was administered to pregnant rats from da y 15 to day 21 of gestation via a chronically implanted subcutaneous osmoti c minipump. Protein expression of leptin and ObR-S in the placenta at day 2 1 of pregnancy was measured by western blotting. Plasma leptin and insulin concentrations were determined by radioimmunoassay and ELISA respectively. Systolic hypertension was measured by tail cuff plethysmography. Results: Dexamethasone administration during the last third of pregnancy de creased placental mass and fetal body weight at day 21 of gestation, caused maternal hyperleptinaemia but fetal hypoleptinaemia, and suppressed placen tal leptin protein expression whilst up-regulating placental protein expres sion of ObR-S. The male and female offspring of dexamethasone-treated dams were hypertensive from 12 weeks of age. One-year-old offspring of dexametha sone-treated dams exhibited significant hyperleptinaemia compared with age- matched controls, an effect associated with hyperinsulinaemia in the male, but not female, offspring. Conclusions: The rat model of maternal dexamethasone treatment is establish ed as a paradigm of 'programmed' hypertension in man. Our data show modific ation of placental leptin and leptin receptor protein expression by dexamet hasone treatment during the last third of pregnancy. We also show that lept in concentrations are suppressed during fetal life but increased in adultho od in this rat model of programmed hypertension. Our data do not necessaril y establish a causal relationship between fetal hypoleptinaemia and impaire d fetal growth during early life, or between hyperleptinaemia and hypertens ion in adulthood. Nevertheless, they suggest that hyperleptinaemia may be a component of the cluster of metabolic abnormalities seen in the insulin re sistance syndrome in man. They also suggest that excessive fetal exposure t o glucocorticoids could be a common early-life stimulus to the association between hyperinsulinaemia, hypertension and hyperleptinaemia often seen in individuals of low birthweight.