Partial Leptin Reduction as an Insulin Sensitization and Weight Loss Strategy

Abstract

Zhao et al. show that in the context of obesity, partial leptin reduction restores hypothalamic leptin sensitivity and leads to reduced food intake, increased energy expenditure, and improved insulin sensitivity. Thus, strategies aimed at partially reducing circulating leptin may represent a promising approach for the treatment of obesity and diabetes. © 2019 Elsevier Inc.The physiological role of leptin is thought to be a driving force to reduce food intake and increase energy expenditure. However, leptin therapies in the clinic have failed to effectively treat obesity, predominantly due to a phenomenon referred to as leptin resistance. The mechanisms linking obesity and the associated leptin resistance remain largely unclear. With various mouse models and a leptin neutralizing antibody, we demonstrated that hyperleptinemia is a driving force for metabolic disorders. A partial reduction of plasma leptin levels in the context of obesity restores hypothalamic leptin sensitivity and effectively reduces weight gain and enhances insulin sensitivity. These results highlight that a partial reduction in plasma leptin levels leads to improved leptin sensitivity, while pointing to a new avenue for therapeutic interventions in the treatment of obesity and its associated comorbidities.