Leptin therapy in patients with lipodystrophy and ayndromic insulin resistance

Leptin in the form of recombinant human methionyl leptin (metreleptin) has now been approved by the FDA for treatment of generalized forms of lipodystrophy. Leptin deficiency plays a major role in the extreme metabolic derangement of lipodystrophy and, therefore, provides a specific drug target. This is one of the best examples of the translation of a fundamental scientific discovery to a drug directly applicable to patients. Leptin therapy in lipodystrophy leads to a major reduction in serum triglycerides, improvement in insulin resistance and diabetes, improvement in nonalcoholic steatohepatitis, reduction in proteinuria, and improvement in menstrual and reproductive function. There is little change in thyroid or adrenal function and very modest change in immune function. In addition to the beneficial effects of metreleptin in generalized lipodystrophy, patients with partial forms of lipodystrophy have similar, albeit more modest responses to leptin, with the best responses seen in those patients with the most severe metabolic derangements. While leptin clearly has effects on satiety it also activates a number of molecules in rodents that affect lipids, insulin sensitivity, and ectopic fat deposition. Greater understanding of these mechanisms in humans will be critical to the further application of leptin to human disease.