Leptin-induced leptin resistant rats exhibit enhanced responses to the melanocortin agonist MT II

The purpose of this study was to determine if leptin could induce a leptin resistance in young rats and if leptin-induced leptin resistant rats are responsive to the melanocortin agonist, melanotan II (MT II). Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control viral vector were administered into young, lean rats for 300 days, and food consumption, body weight, oxygen consumption, serum leptin, and leptin signal transduction were measured. In the rAAV-leptin rats, the anorexic response attenuated by day 140, and the increase in energy expenditure attenuated prior to day 223. At day 300, the rats were challenged with centrally administered recombinant leptin to test leptin responsiveness. Whilst the control responded with a decrease in food intake, the rAAV-leptin rats were unresponsive. The same rats were administered MT II subsequently, and both the leptin-resistant and leptin-responsive groups displayed reduced food intake. Notably, the anorexic response persisted longer in the leptin-resistant group. These data demonstrate that leptin induces leptin resistance in young rats and that these leptin-resistant rats have an enhanced anorexic response to exogenous melanocortin activation. We suggest that defective endogenous melanocortin activation may represent one element of leptin resistance, leading to compensatory hypersensitivity of the melanocortin pathway.