Differential and genetically separable associations of leptin with obesity-related traits

OBJECTIVE: The extent to which leptin protects against obesity is unknown. By intercrossing New Zealand obese mice with lean C57BL/6J mice, we have se parated the genes controlling leptin and other weight-related phenotypes. T his has allowed us to determine whether hyperleptinaemia is associated with reduced food intake and increased physical activity in mice spanning a lar ge range in body weight. METHODS: Plasma leptin, glucose and insulin, body weight, food intake, runn ing wheel activity, and four adipose depots were measured in 587 adult F2 a nd 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 similar to 15 ng/ml, beyond which the relationship reversed. A neg ative relationship was observed between activity and leptin with a maximal decrease in activity once leptin reached similar to 15 ng/ml. CONCLUSION: Leptin has differential responses to food intake and activity, suggesting that it has limited potential to defend against obesity. A genet ic defect in leptin sensitivity is unlikely to be the primary cause of obes ity in these mice, since hyperleptinaemia was not coinherited with both hyp erphagia and inactivity as body weight increased.