OBJECTIVE: Using a recombinant rat leptin antagonist, we investigated the effects of early postnatal leptin disruption on long-term leptin sensitivity and metabolic phenotype. DESIGN: Three groups of 10 newborn female Wistar rats were injected subcutaneously with either saline (control) or leptin antagonist (at 2.5 or 7.5 microg g(-1) day(-1)) from postnatal day 2 to day 13. RESULTS: At weaning (day 28), antagonist-treated rats presented similar body weight (BW) compared to control animals. At 3 months of age, there was no significant change in BW, food intake and leptin or insulin levels between groups. Only a disturbed relationship between circulating insulin and glucose levels was observed in antagonist-treated animals. At 4 months of age, treated animals developed a leptin resistance appreciated by the lack of response to a 7-days leptin treatment (1 mg kg(-1) day(-1)) in term of decrease in food intake and BW. At 8 months of age, following 3 months of high-energy diet, rlepm7.5 animals presented higher BW gain associated with increased body fatness and striking hyperleptinaemia as compared to control animals. CONCLUSION: The blockage of leptin action during the critical period of early life in rodents has long-term consequences by altering the capacity to respond to leptin during adulthood, thus predisposing the animals to obesity. These findings clearly demonstrate the physiological importance of the postnatal leptin surge for the optimal onset of the metabolic regulation, at least in rodents, and its implication in the prevention of unfavourable developmental programming.