Context: Cannabinoid CB₁ 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 β-cells.

Design, Setting, and Patients: Mouse 3T3-F442A adipocytes and rat insulinoma RIN-m5F β-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/m², and serum from normoglycemic and type 2 diabetes patients were studied.

Main Outcome Measure: 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 β-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 β-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. CB₁ receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F β-cells kept in high glucose.

Conclusions: Peripheral endocannabinoid overactivity might explain why CB₁ blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.