Partial Leptin Reduction as an Insulin Sensitization and Weight Loss Strategy

Summary The physiological role of leptinis thought to be a driving force to reduce food intake and increase energy expenditure. However, leptintherapies in the clinic have failed to effectively treat obesity, predominantly due to a phenomenon referred to as leptinresistance. The mechanisms linking obesity and the associated leptinresistance 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 leptinlevels in the context of obesity restores hypothalamic leptinsensitivity and effectively reduces weight gain and enhances insulin sensitivity. These results highlight that a partial reduction in plasma leptinlevels leads to improved leptinsensitivity, while pointing to a new avenue for therapeutic interventions in the treatment of obesity and its associated comorbidities.