Partial Leptin Reduction as an Insulin Sensitization and Weight Loss Strategy

Cell Metab. 2019 Oct 1;30(4):706-719.e6. doi: 10.1016/j.cmet.2019.08.005. Epub 2019 Sep 5.


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.

Keywords: diabetes; hypothalamus; leptin; leptin resistance; obesity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology*
  • Antibodies, Neutralizing / therapeutic use
  • Eating / drug effects
  • Energy Metabolism / drug effects
  • Insulin / metabolism*
  • Insulin Resistance*
  • Leptin / antagonists & inhibitors*
  • Leptin / blood
  • Mice
  • Mice, Inbred Strains
  • Obesity / metabolism
  • Obesity / therapy*
  • Weight Loss / drug effects*
  • Weight Reduction Programs / methods*


  • Antibodies, Neutralizing
  • Insulin
  • Leptin