20 YEARS OF LEPTIN: Leptin in common obesity and associated disorders of metabolism

The molecular mechanisms of body weight and body composition regulation have long been a research focus in the hopes of identifying tractable pathways for therapeutic interventions for obesity and diabetes, as well as related disorders such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and polycystic ovary syndrome. The metabolic consequences of obesity and type 2 diabetes (T2D) were already a focus of the world's attention in 1994 when the discovery of leptin generated enormous enthusiasm for the potential to treat common (non-monogenic) obesity and its associated metabolic disorders with an adipokine hormone that regulated body weight as well as lipid and carbohydrate metabolism. Recombinant human leptin and many leptin analogs were developed and studied in animals and a few in human clinical trials. Overall, the opportunity for leptin as a therapeutic in unselected patients with obesity and T2D has not been substantiated in clinical trials. The potential for combination therapy suggested by clinical studies with leptin and pramlintide supports a path toward obesity treatment through the leptin pathway. The profound metabolic benefits seen with leptin in numerous forms of leptin deficiency, including lipodystrophy, provide hope for the opportunity to identify selected subsets of patients who could benefit from leptin treatment. This review provides a comprehensive overview of the clinical data on a subset of the potential utilities of leptin, specifically as a therapeutic for general or common obesity and its metabolic consequences including T2D and NAFLD/NASH.