Obesity and diabetes are major public health threats worldwide. Insulin resistance appears to be a significant factor in this global epidemic. In this present review, we have focused on a human model of insulin resistance which embodies many of the metabolic abnormalities that are associated with the morbidity of diabetes and obesity. Lipodystrophy in rodents and humans is a severe model of insulin resistance, and we use a novel therapeutic approach with the administration of the newly discovered leptin to ameliorate many of these metabolic abnormalities. The ability to study the administration of leptin in this setting of severe insulin resistance allows us perform a coveted look into a human condition where metabolic dysfunction can be reversed or controlled.