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OBJECTIVE: The extent to which leptin protects against obesity is unknown. By intercrossing New Zealand obese mice with lean C57BL/6J mice, we have separated the genes controlling leptin and other weight-related phenotypes. This has allowed us to determine whether hyperleptinaemia is associated with reduced food intake and increased physical activity in mice spanning a large range in body weight. METHODS: Plasma leptin, glucose and insulin, body weight, food intake, running wheel activity, and four adipose depots were measured in 587 adult F2 and backcross mice RESULTS: When mice were categorized by adiposity, a plot of food intake vs leptin illustrated a U-shaped curve. Food intake decreased as leptin levels rose to ∼15 ng/ml, beyond which the relationship reversed. A negative relationship was observed between activity and leptin with a maximal decrease in activity once leptin reached ∼15 ng/ml. CONCLUSION: Leptin has differential responses to food intake and activity, suggesting that it has limited potential to defend against obesity. A genetic defect in leptin sensitivity is unlikely to be the primary cause of obesity in these mice, since hyperleptinaemia was not coinherited with both hyperphagia and inactivity as body weight increased. [ABSTRACT FROM AUTHOR]