This study aimed to determine for the first time whether leptin can act to alter the structural and functional characteristics of adipose tissue before birth. Leptin (0.48 mg/kg/day) or saline was infused intravenously into fetal sheep for 4 days from either 136 or 137 days of gestation (term=147+/-3 days). Circulating leptin concentrations were increased approximately four- to fivefold by leptin infusion. Leptin infusion resulted in a significant increase in the proportion of smaller lipid locules present within fetal perirenal adipose tissue (PAT), and this was associated with a significant increase in the proportion of multilocular tissue and a significant decrease in the proportion and relative mass of unilocular tissue in fetal PAT. The relative abundance of leptin mRNA in fetal PAT was significantly lower in the leptin-infused group, and there was a positive correlation between the relative abundance of leptin mRNA and the proportion of unilocular adipose tissue in fetal PAT. The amount of uncoupling protein 1 tended to be higher (P=0.06) in leptin-infused compared with saline-infused fetuses. This is the first demonstration that leptin can act to regulate the lipid storage characteristics, leptin synthetic capacity, and potential thermogenic functions of fat before birth.