In fetal sheep, adipose leptin mRNA and plasma leptin levels increase near term in parallel with the prepartum cortisol surge (Yuen et al. 1999; Forhead et al. 2001). However, the developmental control of circulating leptin by glucocorticoids in utero is unknown. This study investigated the effects of adrenalectomy and glucocorticoid infusion on plasma leptin concentration in chronically catheterised fetal sheep during late gestation.

All procedures were carried out according to UK legislation. Under halothane anaesthesia (1.5 % in O₂-N₂O), vascular catheters were implanted into 33 sheep fetuses at least 3 days before sampling began. Where possible, in fifteen fetuses, daily arterial blood samples were taken from 133 days until 137-142 days of gestation (term 145 ± 2 days); five of these fetuses were adrenalectomised (AX) previously at 120-123 days. The remaining 18 fetuses were infused I.V. from 123-127 days with either saline (0.9 % NaCl, n = 6) or cortisol (3-5 mg kg^-1 day^-1, n = 6) for 5 days, or with dexamethasone (DEX, 45-60 µg kg^-1 day^-1, n = 6) for 2 days. The cortisol dose increased the plasma cortisol concentration to that normally seen near term, and the DEX dose led to a plasma DEX concentration around one-fifth of that measured in human infants delivered after maternal DEX treatment. Arterial blood samples were taken daily from 2 days before and throughout the infusion. Plasma leptin and cortisol were determined by ELISA and RIA, respectively. Data (means ± S.E.M.) were log₁₀-transformed where appropriate, and were analysed by either one-way or two-way ANOVA with repeated measures followed by the Fisher test.

Towards term, significant increases in both plasma cortisol and leptin concentrations occurred in the untreated intact, but not AX, fetuses (P < 0.05). In the untreated intact fetuses, plasma leptin increased from 231 ± 8 pg ml^-1 at 133 days to a maximum of 405 ± 89 pg ml^-1 at 139 days of gestation (P < 0.05). Saline infusion had no effect on plasma leptin: values remained within the basal range of 133 ± 18 pg ml^-1. Within 1 day of glucocorticoid infusion, plasma leptin concentration increased from 216 ± 42 to 468 ± 81 pg ml^-1 (+127 ± 21 %, P < 0.05) in the cortisol-infused fetuses, and from 128 ± 14 to 457 ± 76 pg ml^-1 (+268 ± 61 %, P < 0.05) in the DEX-infused fetuses. However, the rise in plasma leptin was not maintained throughout the cortisol infusion; by the fifth day of infusion, plasma leptin was restored to within the basal range. In the DEX-infused fetuses, the mean plasma leptin concentration observed on the second day of infusion (274 ± 27 pg ml^-1) remained above the basal values (P < 0.05).

Therefore, in the sheep fetus, the adrenal gland is required for the normal ontogenic increase in plasma leptin seen near term. Furthermore, exogenous and endogenous glucocorticoids increase the circulating leptin concentration in utero.

This work was supported by the BBSRC and Tommy’s Campaign.