The CB-1 receptor antagonist rimonabant modulates the interaction between adipocytes and pancreatic beta-cells in vitro.
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.
Ülgen
F
F
Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany.
Kühn
M C
MC
Cupisti
K
K
Herder
C
C
Willenberg
H S
HS
Schott
M
M
Scherbaum
W A
WA
Schinner
S
S
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
D052242:Adiponectin; D063387:Cannabinoid Receptor Antagonists; D007328:Insulin; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant