title: Endocannabinoids regulate adipokine production and the immune balance of omental adipose tissue in human obesity.
abstract: OBJECTIVE
  (1) To investigate whether modulation of the cannabinoid type 1 receptor (CB1R) directly regulates the production of adiponectin (ApN) and other adipokines in omental adipose tissue (OAT) of obese subjects, (2) to establish in which cellular fraction of OAT the effects of CB1R blockade take place and (3) to unravel the underlying mechanisms.
  
  
  METHODS
  OAT was obtained from 30 obese subjects (body mass index: 40.6±1.3 kg m(-2)) undergoing abdominal surgery. Primary cultures of explants or of freshly isolated adipocytes or stromal-vascular cells (SVCs) were used.
  
  
  RESULTS
  In OAT explants, the CB1R blocker Rimonabant upregulated ApN gene expression. mRNA abundance of omentin that exhibits insulin-sensitizing properties was upregulated as well. Conversely, mRNA levels of two pro-inflammatory cytokines, macrophage inflammatory protein (MIP)-1β and interleukin (IL)-7 were downregulated. We next examined where these effects took place within OAT. CB1R expression was similar in both cellular fractions. In isolated mature adipocytes, blockade of CB1R reproduced the increase of ApN mRNA and the decrease of IL-7 mRNA, while inducing a rise of ApN secretion into the medium. In isolated SVC, gene expression of omentin, which is restricted to this fraction, was augmented, while that of MIP-1β was diminished. Finally, we deciphered the mechanisms leading to ApN regulation by the endocannabinoid system (ES). We first established that ApN regulation was actually mediated by the CB1R: ApN gene expression was upregulated by Rimonabant and downregulated by the CB1R agonist arachidonyl-2-chloroethylamide (ACEA). Upregulation of ApN by Rimonabant was unaltered by inhibiting cAMP production. However, downregulation of ApN by ACEA was fully reversed by an inhibitor of p38 mitogen-activated protein kinase (p38MAPK) and ACEA increased p38MAPK phosphorylation.
  
  
  CONCLUSIONS
  Blockade of CB1R attenuates the inflammatory state in both cellular fractions of OAT either by increasing ApN and omentin production or by decreasing mRNAs of MIP-1β and IL-7. ApN regulation by the ES partly involves p38MAPK.
authors.affiliation: Endocrinology, Diabetes and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, University of Louvain, Brussels, Belgium.
authors.forename: Q
authors.initials: Q
authors.lastname: Ge
authors.forename: E
authors.initials: E
authors.lastname: Maury
authors.forename: L
authors.initials: L
authors.lastname: Rycken
authors.forename: J
authors.initials: J
authors.lastname: Gérard
authors.forename: L
authors.initials: L
authors.lastname: Noël
authors.forename: R
authors.initials: R
authors.lastname: Detry
authors.forename: B
authors.initials: B
authors.lastname: Navez
authors.forename: S M
authors.initials: SM
authors.lastname: Brichard
mesh_terms: D050153:Abdominal Fat / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017667:Adipocytes / Q000276:immunology / Q000378:metabolism*; D054392:Adipokines / Q000096:biosynthesis; D052242:Adiponectin / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D015153:Blotting, Western; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000276:immunology / Q000378:metabolism* / Q000601:surgery; D009852:Omentum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism*; D000077285:Rimonabant; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D054392:Adipokines; D052242:Adiponectin; C066507:CCL4 protein, human; D063387:Cannabinoid Receptor Antagonists; D054407:Chemokine CCL4; D053583:Interleukin-1beta; D015851:Interleukin-7; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D048051:p38 Mitogen-Activated Protein Kinases; D000077285:Rimonabant