Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia.
BACKGROUND
Cannabinoid CB(1) receptor blockade decreases weight and hyperinsulinemia in obese animals and humans in a way greatly independent from food intake.


OBJECTIVE
The objective of this study was to investigate the regulation and function of the endocannabinoid system in adipocytes and pancreatic beta-cells.


METHODS
Mouse 3T3-F442A adipocytes and rat insulinoma RIN-m5F beta-cells, pancreas and fat from mice with diet-induced obesity, visceral and sc fat from patients with body mass index equal to or greater than 30 kg/m(2), and serum from normoglycemic and type 2 diabetes patients were studied.


METHODS
Endocannabinoid enzyme and adipocyte protein expression, and endocannabinoid and insulin levels were measured.


RESULTS
Endocannabinoids are present in adipocytes with levels peaking before differentiation, and in RIN-m5F beta-cells, where they are under the negative control of insulin. Chronic treatment of adipocytes with insulin is accompanied by permanently elevated endocannabinoid signaling, whereas culturing of RIN-m5F beta-cells in high glucose transforms insulin down-regulation of endocannabinoid levels into up-regulation. Epididymal fat and pancreas from mice with diet-induced obesity contain higher endocannabinoid levels than lean mice. Patients with obesity or hyperglycemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls. CB(1) receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F beta-cells kept in high glucose.


CONCLUSIONS
Peripheral endocannabinoid overactivity might explain why CB(1) blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.
Matias
Isabel
I
Endocannabinoid Research Group, Institute of Biomolecular Chemistry of the National Research Council, via Campi Flegrei 34, 80078 Pozzuoli (Naples), Italy.
Gonthier
Marie-Paule
MP
Orlando
Pierangelo
P
Martiadis
Vassilis
V
De Petrocellis
Luciano
L
Cervino
Cristina
C
Petrosino
Stefania
S
Hoareau
Laurence
L
Festy
Franck
F
Pasquali
Renato
R
Roche
Regis
R
Maj
Mario
M
Pagotto
Uberto
U
Monteleone
Palmiero
P
Di Marzo
Vincenzo
V