Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance

Cell Metab. 2012 Aug 8;16(2):167-79. doi: 10.1016/j.cmet.2012.07.002. Epub 2012 Jul 26.


Obesity-related leptin resistance manifests in loss of leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Anti-Obesity Agents / chemistry
  • Anti-Obesity Agents / pharmacology*
  • Anti-Obesity Agents / therapeutic use
  • Body Weight / drug effects
  • Drug Inverse Agonism
  • Drug Resistance / drug effects*
  • Fatty Liver / drug therapy*
  • Fatty Liver / etiology
  • Insulin Resistance
  • Leptin / metabolism*
  • Mice
  • Molecular Structure
  • Obesity / complications
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Receptor, Cannabinoid, CB1 / agonists*
  • Regression Analysis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use


  • Anti-Obesity Agents
  • Cnr1 protein, rat
  • Leptin
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Sulfonamides
  • JD5037