Leptin applications in 2015: what have we learned about leptin and obesity?

Abstract

Purpose of review: To summarize previous and current advancements for leptin therapeutics, we described how leptin may be useful in leptin deficient states such as lipodystrophy, for which leptin was recently approved, and how it may be useful in the future for typical obesity.

Recent findings: The discovery of leptin in 1994 built the foundation for understanding the pathophysiology and treatment of obesity. Leptin therapy reverses morbid obesity related to congenital leptin deficiency and appears to possibly treat lipodystrophy, a finding which has led to the approval of leptin for the treatment of lipodystrophy in the USA and Japan. Typical obesity, on the other hand, is characterized by hyperleptinemia and leptin tolerance. Thus, leptin administration has proven ineffective for inducing weight loss on its own but could possibly be useful in combination with other therapies or for weight loss maintenance.

Summary: Leptin is not able to treat typical obesity; however, it is effective for reversing leptin deficiency-induced obesity and is possibly useful in lipodystrophy. New mechanisms and pathways involved in leptin resistance are continuously discovered, whereas the development of new techniques and drug combinations which may improve leptin's efficacy and safety regenerate the hope for its use as an effective treatment for typical obesity.

Figures

Figure 1. Leptin dimerizes the leptin receptor (LepR) and activates a number of intracellular signaling molecules

JAK2 phosphorylates three tyrosine sites on the LepR and activates STAT3, which inhibits melanocortin, PI3K, which in turn acts on the insulin receptor, AKT, and mTOR pathways, and STAT5, whose function is not yet well defined. At Tyr985, SOCS3 and SHP2 both feedback to inhibit JAK2, and SHP2 activates ERK pathways. At Tyr1077, STAT5 activation leads to gene expression changes. At Tyr1138, STAT3 alters gene expression and activates SOCS3, which feeds back to inhibit JAK2.