Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis.
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.
Deveaux
Vanessa
V
INSERM, U955, Créteil, France.
Cadoudal
Thomas
T
Ichigotani
Yasukatsu
Y
Teixeira-Clerc
Fatima
F
Louvet
Alexandre
A
Manin
Sylvie
S
Nhieu
Jeanne Tran-Van
JT
Belot
Marie Pierre
MP
Zimmer
Andreas
A
Even
Patrick
P
Cani
Patrice D
PD
Knauf
Claude
C
Burcelin
Remy
R
Bertola
Adeline
A
Le Marchand-Brustel
Yannick
Y
Gual
Philippe
P
Mallat
Ariane
A
Lotersztajn
Sophie
S
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
D020738:Leptin; D014280:Triglycerides