We identified that leptin resistance in aged-obese rats has both peripheral and central components. The central resistance is characterized by diminished hypothalamic leptin receptors and impaired leptin signal transduction. We developed a new model of leptin-induced leptin resistance in which application of the central leptin gene delivery produces unabated hypothalamic leptin over-expression. The chronic central elevation of leptin precipitates leptin resistance in young animals devoid of obesity and exacerbates it in mature or aged animals with obesity. Despite leptin resistance, our aged obese, DIO, and leptin-induced leptin resistant rats were fully responsive to central pharmacological melanocortin activation. We propose that the central leptin resistance resides between leptin receptor and melanocortin receptor activation. Our central POMC gene therapy overcame leptin resistance, producing weight and fat loss and improved insulin sensitivity in obese Zucker and aged rats. This success highlights the central melanocortin system as a useful drug target for combating obesity.