title: Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis.
abstract: BACKGROUND
  Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver.
  
  
  METHODS
  Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-).
  
  
  RESULTS
  In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice.
  
  
  CONCLUSIONS
  These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorders.
authors.affiliation: INSERM, U955, Créteil, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Deveaux
authors.forename: Thomas
authors.initials: T
authors.lastname: Cadoudal
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Ichigotani
authors.forename: Fatima
authors.initials: F
authors.lastname: Teixeira-Clerc
authors.forename: Alexandre
authors.initials: A
authors.lastname: Louvet
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manin
authors.forename: Jeanne Tran-Van
authors.initials: JT
authors.lastname: Nhieu
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Belot
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Patrick
authors.initials: P
authors.lastname: Even
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
authors.forename: Remy
authors.initials: R
authors.lastname: Burcelin
authors.forename: Adeline
authors.initials: A
authors.lastname: Bertola
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.forename: Ariane
authors.initials: A
authors.lastname: Mallat
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005234:Fatty Liver / Q000150:complications / Q000628:therapy*; D007249:Inflammation; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000628:therapy*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D020738:Leptin; D014280:Triglycerides