title: The CB-1 receptor antagonist rimonabant modulates the interaction between adipocytes and pancreatic beta-cells in vitro.
abstract: BACKGROUND
  Adipocytes produce signalling molecules which can act on target cells including pancreatic beta-cells. In previous studies we found adipocytes to directly stimulate insulin secretion and the proliferation of pancreatic beta-cells in vitro. Rimonabant acts as an antagonist at the cannabinoid-1 (CB-1) receptor which is expressed on adipocytes. Rimonabant decreases insulin levels in vivo. This effect can either be explained by improving insulin sensitivity or by effects on beta-cells including the modulation of adipocyte - beta-cell interactions.
  
  
  OBJECTIVE
  To test how pre-treatment of primary human adipocytes with rimonabant affects the cross-talk between adipocytes and pancreatic beta-cells in vitro.
  
  
  RESULTS
  Rimonabant had no direct effect on insulin secretion or beta-cell proliferation at a concentration range from 1 nM to 1 μM. This is in line with previous findings showing that in the murine pancreas CB-1 receptors are preferentially expressed on non-beta-cells, while rimonabant is a selective blocker of CB-1 receptors. We found fat-cell conditioned-medium without (FCCM) and after pre-treatment for 24 h with 100 nM rimonabant (FCCM-RB) to induce insulin secretion from primary murine beta-cells to a similar extent. Proliferation of a pancreatic beta-cell line was enhanced by FCCM to 219%, while FCCM-RB inhibited proliferation to 53%. As we previously found Wnt-signalling to mediate effects of adipocytes on beta-cell proliferation we tested the ability of FCCM and FCCM-RB to activate canonical Wnt-signalling in target cells. However, there was no significant difference between the groups: FCCM and FCCM-RB stimulated Wnt reporter gene activity to 181% and 179%, respectively. In addition, there was no significant difference in adiponectin levels between FCCM and FCCM-RB (56.8 vs. 58.1 ng/ml), showing that adiponectin does not mediate the differential effects on beta-cell proliferation by FCCM and FCCM-RB.
  
  
  CONCLUSIONS
  Our data show that rimonabant modulates the adipocyte - beta-cell interaction with respect to beta-cell proliferation and indicate that signalling molecules other than adiponectin and components of the Wnt pathway mediate this cross-talk.
authors.affiliation: Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Ülgen
authors.forename: M C
authors.initials: MC
authors.lastname: Kühn
authors.forename: K
authors.initials: K
authors.lastname: Cupisti
authors.forename: C
authors.initials: C
authors.lastname: Herder
authors.forename: H S
authors.initials: HS
authors.lastname: Willenberg
authors.forename: M
authors.initials: M
authors.lastname: Schott
authors.forename: W A
authors.initials: WA
authors.lastname: Scherbaum
authors.forename: S
authors.initials: S
authors.lastname: Schinner
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D000077285:Rimonabant; D018709:Statistics, Nonparametric
chemical_list: D052242:Adiponectin; D063387:Cannabinoid Receptor Antagonists; D007328:Insulin; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant