Low plasma leptin levels have been shown to be associated with the development of obesity in mice as well as in humans. The present study was undertaken to determine if raising plasma leptin levels of obesity-prone C57BL/6J (B6) mice to those seen in obesity-resistant A/J mice would prevent the development of diet-induced obesity. Four-week-old B6 (n = 40) and A/J (n = 10) male mice were weaned onto a low-fat (11% kcal) diet. When the animals weighed 20 g, their diets were changed to a high-fat (HF) diet (58% kcal), and a continuous infusion of leptin (0.4 mg x kg(-1) x day(-1)) or phosphate-buffered saline (control) was started using Alzet minipumps. The A/J mice were not treated but were included to monitor the efficacy of the minipumps in raising plasma leptin in B6 mice. The mice were followed for 12 weeks. Chronic treatment with leptin for 4 weeks raised plasma levels in B6 mice to that of A/J mice. Plasma leptin in B6 control mice remained significantly lower than A/J mice through week 4. By week 8, leptin levels in the B6 control group had risen and were similar to A/J mice. Although there were significant weight differences between B6 treated and B6 control groups for 2-3 weeks after pump implantation, these differences were transient. Ultimately, there were no weight differences between the B6 treated and B6 control groups. There were no differences in plasma glucose between B6 treated and control groups. Plasma insulin values were also not different between the 2 groups. There was no effect of leptin supplementation on locomotor activity or food intake in B6 mice. In summary, this study demonstrates that leptin supplementation in animals that show low plasma leptin levels in response to fat feeding may slow but does not prevent the subsequent development of diet-induced obesity.