Leptin Therapy in People with a Normal Leptin Gene

Abstract

Two decades have passed since the paradigm-changing discovery in 1994 that mutations in the ob gene (aka lep) lead to murine morbid obesity. The OB receptor (aka lepr) and natural ligand, leptin, were identified the following year. Early proof-of-concept studies in rodents and humans with homozygous ob mutations subsequently heralded the possibility that exogenously administered leptin might prove a useful therapeutic in obese humans with a normal leptin gene. Unlike the low or absent leptin blood levels observed in the presence of ob mutations, most obese subjects have relatively high circulating leptin levels, a finding suggesting that the majority of people with excess adiposity are insensitive to the hormone’s actions in vivo. Two forms of leptin were developed for proof-of-concept human studies, recombinant methionyl leptin (metreleptin), and pegylated recombinant human leptin (PEG-OB). Both the pivotal metreleptin and PEG-OB randomized double-blind placebo-controlled studies showed modest but statistically significant weight loss in overweight and obese subjects at relatively high subcutaneously administered doses. A wide range of secondary outcomes were evaluated, although most reported studies were post-hoc analyses and not designed to specifically test a selective leptin effect. While exogenously administered leptin safely promotes weight loss in obese humans with a normal leptin gene, efficacy is modest and thus little clinical value can be ascribed to this treatment approach across the population as a whole. Strategies for overcoming the insensitivity to leptin’s actions in the presence of excess adiposity are needed for this hormonal mechanism to prove useful as a clinical therapeutic.