title: Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance.
abstract: 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.
authors: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. tamy@mail.nih.gov
authors: Joseph
authors: J
authors: Tam
authors: Resat
authors: R
authors: Cinar
authors: Jie
authors: J
authors: Liu
authors: Grzegorz
authors: G
authors: Godlewski
authors: Daniel
authors: D
authors: Wesley
authors: Tony
authors: T
authors: Jourdan
authors: Gergő
authors: G
authors: Szanda
authors: Bani
authors: B
authors: Mukhopadhyay
authors: Lee
authors: L
authors: Chedester
authors: Jeih-San
authors: JS
authors: Liow
authors: Robert B
authors: RB
authors: Innis
authors: Kejun
authors: K
authors: Cheng
authors: Kenner C
authors: KC
authors: Rice
authors: Jeffrey R
authors: JR
authors: Deschamps
authors: Robert J
authors: RJ
authors: Chorvat
authors: John F
authors: JF
authors: McElroy
authors: George
authors: G
authors: Kunos
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D054314:Drug Inverse Agonism; D004351:Drug Resistance / Q000187:drug effects*; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D012044:Regression Analysis; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; C543264:Cnr1 protein, rat; D020738:Leptin; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; C577200:JD5037