Leptin expression in the fetus is altered by different intrauterine conditions, and these responses vary according to the nature of the stressor. Table 2 summarises the effects of a variety of experimental manipulations on plasma leptin concentration and adipose leptin gene expression in the ovine fetus. Moderate changes in maternal nutrition do not appear to affect tissue leptin expression or circulating leptin in fetal sheep. While maternal undernutrition influences plasma leptin in the pregnant ewe, there is little change in plasma leptin or adipose leptin mRNA abundance in the fetus (Yuen et al. 2002; Ehrhardt et al. 2002; Edwards et al. 2005). Maternal overnutrition increases leptin gene expression in fetal adipose tissue, without affecting plasma leptin concentration (Muhlhausler et al. 2002, 2007). In this study, adipose leptin mRNA abundance was positively correlated with plasma insulin concentration in utero (Muhlhausler et al. 2007). Indeed, leptin gene expression in adipose tissue is clearly regulated by circulating insulin in the fetus as in the adult animal. In fetal sheep, chronic hyperglycaemia and hyperinsulinaemia causes an increase in adipose leptin mRNA, while hypoglycaemia and hypoinsulinaemia leads to a reduction in adipose leptin mRNA levels (Devaskar et al. 2002). Similarly, in acute studies, hyperinsulinaemia with euglycaemia causes a two-fold increase in leptin gene expression in fetal adipose tissue, whereas hyperglycaemia with euinsulinaemia has no effect on adipose leptin mRNA abundance (Devaskar et al. 2002).
Placental insufficiency induced in sheep by carun-clectomy causes a decrease in leptin mRNA expression in perirenal adipose tissue of the fetus with no change in circulating leptin concentration (Duffield et al. 2008). Suppression of leptin gene expression in this model of intrauterine undernutrition and growth retardation may be due to low plasma concentrations of insulin and glucose in utero (Duffield et al. 2008). In contrast, chronic undernutrition of the ovine fetus by occlusion of the uterine artery and a reduction in uterine blood flow leads to a rise in plasma leptin concentration (Buchbinder et al. 2001). Likewise, elevated plasma leptin, when expressed on a weight-specific basis, has been reported in growth-retarded human fetuses with lactacidaemia and abnormal Doppler imaging of the umbilical cord (Cetin et al. 2000). Stimulation of plasma leptin during fetal distress may be related to changes in oxygen availability and/or adrenocortical activity since plasma leptin in sheep fetuses has been shown to correlate inversely with the arterial partial pressure of oxygen and positively with plasma cortisol concentration (Forhead et al. 2002). Long-term hypoxia induced in sheep at high altitude for most of gestation increases plasma leptin in the fetus, and gene expression of leptin in placenta and fetal adipose tissue, without any change in plasma glucose or insulin concentrations (Ducsay et al. 2006). Glucocorticoids modify leptin expression before and after birth: in fetal sheep, leptin mRNA abundance in adipose tissue, and circulating leptin concentration, are increased by cortisol and dexamethasone treatment, and suppressed by fetal adrenalectomy (O'Connor et al. 2007). Interestingly, however, maternal dexamethasone administration in pregnant rats decreases leptin concentration in the fetal circulation in association with changes in placental leptin receptor expression and reductions in placental content and transfer of leptin (Sudgen et al. 2001; Smith & Waddell, 2002, 2003). Thyroid hormones also affect circulating and adipose levels of leptin before birth. Hypothyroidism in the ovine fetus near term, induced by thyroidectomy, increases plasma leptin and leptin mRNA abundance in fetal adipose tissue (O'Connor et al. 2007). Moreover, leptin synthesis by fetal adipose tissue shows negative feedback control to regulate circulating concentrations. Intravenous infusion of recombinant ovine leptin in fetal sheep reduces leptin mRNA abundance in perirenal adipose tissue (Yuen et al. 2003). It is also apparent that circulating leptin concentration in utero may depend upon the breed, and genetic background, of the sheep used in experimental studies. The Welsh Mountain fetus has lower plasma leptin concentration to the Merino fetus, and the developmental increase in adipose leptin mRNA abundance seen in both breeds near term is accompanied by a rise in plasma leptin in the fetuses of the Welsh Mountain, but not Merino breed (Yuen et al. 1999, 2004; Forhead et al. 2002; O'Connor et al. 2007). These differences may reflect the amount, and secretory capacity, of adipose tissue in the fetuses of different sheep breeds and the physiological consequences of breeding sheep for different environmental conditions. Therefore, leptin synthesis and circulating concentration in utero respond to a range of nutrient, hormonal and genetic influences, although little is known about how these factors affect the expression of leptin receptors in fetal tissues. Leptin may be one of a number of hormones, including insulin, glucocorticoids and thyroid hormones, that signal changes in the intrauterine environment and, in turn, govern appropriate responses in growth and development in fetal tissues.