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

Abstract

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, leptin concentrations in adulthood are inversely related to body weight at birth, independent of adult adiposity, and correlate with fasting insulin. Glucocorticoids and insulin regulate leptin secretion. Excessive exposure to glucocorticoids 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 hypertension. Objective: To determine whether IUGR induced by maternal glucocorticoid treatment during the last third of pregnancy in the rat is associated with modulation of either maternal or fetal leptin concentrations, the placental expression of leptin or the short form of the leptin receptor (ObR-S), or combinations thereof, and to evaluate whether hypertension or hyperinsulinaemia in the earlygrowth-retarded adult progeny of dexamethasone-treated dams is associated with altered leptin concentrations. Design and Methods: Dexamethasone was administered to pregnant rats from day 15 to day 21 of gestation via a chronically implanted subcutaneous osmotic minipump. Protein expression of leptin and ObR-S in the placenta at day 21 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 decreased placental mass and fetal body weight at day 21 of gestation, caused maternal hyperleptinaemia but fetal hypoleptinaemia, and suppressed placental leptin protein expression whilst up-regulating placental protein expression of ObR-S. The male and female offspring of dexamethasone-treated dams were hypertensive from 12 weeks of age. One-year-old offspring of dexamethasone-treated dams exhibited signi®cant 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 established as a paradigm of programmed' hypertension in man. Our data show modi®cation of placental leptin and leptin receptor protein expression by dexamethasone treatment during the last third of pregnancy. We also show that leptin concentrations are suppressed during fetal life but increased in adulthood in this rat model of programmed hypertension. Our data do not necessarily establish a causal relationship between fetal hypoleptinaemia and impaired fetal growth during early life, or between hyperleptinaemia and hypertension in adulthood. Nevertheless, they suggest that hyperleptinaemia may be a component of the cluster of metabolic abnormalities seen in the insulin resistance syndrome in man. They also suggest that excessive...

Monitoring blood plasma leptin and lactogenic hormones in pregnant sows

“…During pregnancy, glucocorticoids belong to factors that reduce insulin sensitivity in the dam, activate adipogenesis by differentiation of pre-adipocytes (Breton, 2013) and promote, in sheep, the synthesis and secretion of leptin in the fetus (Forhead and Fowden, 2009). It has been suggested that the glucocorticoid surge that is characteristic of late gestation may also downregulate placental leptin production (Sugden et al, 2001). Changes in either fetal or maternal leptin levels may be important for parturition or late fetal development.…”

Leptin receptor expression in fetal lung increases in late gestation in the baboon: a model for human pregnancy

“…Other regulatory parallels include the effects of glucocorticoids, which in addition to up-regulating the putative FPF in the lung (Bolt et al 2001), increase leptin synthesis and release by human adipocytes (Leal-Cerro et al 2001), and enhance leptin levels in preterm infants (Ng et al 2002). Moreover, the co-culture of human placental trophoblast cells with glucocorticoids has been observed to enhance leptin release (Coya et al 2001), while maternal glucocorticoid treatment resulted in an up-regulation of placental leptin receptor protein in rat pregnancy (Sugden et al 2001). Therefore, with respect to: (i) the effects of androgens and glucocorticoids; (ii) the common tissues of origin of both leptin and the putative regulator; and (iii) the similarities in the molecular masses of leptin and the proposed FPF (Bergen et al 2002, Torday & Rehan 2002, leptin has been suggested by as a logical FPF candidate.…”

Maternal influences on epigenetic programming of the developing hypothalamic‐pituitary‐adrenal axis

“…Indeed, stress-induced high levels of maternal glucocorticoids can cross the placenta (Takahashi et al, 1998). DEX readily crosses the placenta and is not inactivated by 11bHSD2, suggesting that bypassing this system may contribute to low birth weight and fetal programming of hypertension (Benediktsson et al, 1993;Nyirenda et al, 1998;Sugden et al, 2001). In further support of this idea, inhibition of 11bHSD2 by carbenoxolone during gestation produces hypertension in adult offspring (Langley-Evans, 1997).…”

“…Other outcomes associated with these maternal treatments are altered insulin sensitivity (Ozanne et al, 1996;Sugden and Holness, 2002;Fernandez-Twinn et al, 2005), increased fat deposition (Bellinger et al, 2006), and impaired renal function (Woods et al, 2004). It is unclear whether fetal programming stems primarily from nutritional status or through endocrine alterations in the mother and fetus (or both) because prenatal glucocorticoid exposure produces metabolic effects similar to those seen in IUGR models (Benediktsson et al, 1993;Nyirenda et al, 1998;Sugden et al, 2001;Tamashiro et al, 2009). …”

“…The synthetic glucocorticoid DEX has been shown to reduce birth weight (Nyirenda et al, 1998) and cause adult hypertension in maternally exposed rat offspring (Benediktsson et al, 1993;Sugden et al, 2001). Basal CORT levels are elevated and hippocampal mineralocorticoid receptor (MR) and GR mRNA expression is reduced in adult rats prenatally exposed to DEX, suggesting that these receptors may be key in the programming effects (Levitt et al, 1996).…”