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Regulation, Function, and Dysregulation of Endocannabinoids in Models of Adipose and ß-Pancreatic Cells and in Obesity and Hyperglycemia

Endocannabinoid Research Group (I.M., P.O., L.D.P., S.P., V.D.M.) at the Institutes of Biomolecular Chemistry (I.M., S.P., V.D.M.), Biochemistry of Proteins (P.O.), and Cybernetics (L.D.P.), National Research Council, 80078 Pozzuoli (NA), Italy; Université de La Réunion (M.-P.G., L.H., F.F., R.R.), 97715 La Réunion, France; Department of Psychiatry (V.M., M.M., P.M.), Second University of Naples, 80138 Naples, Italy; and Endocrinology Unit (C.C., R.P., U.P.), Department of Internal Medicine and Gastroenterology, Center of Applied Biomedical Research, S. Orsola-Malpighi General Hospital, 40138 Bologna, Italy

Address all correspondence and requests for reprints to: Vincenzo Di Marzo, Ph.D., Endocannabinoid Research Group, Institute of Biomolecular Chemistry of the National Research Council, via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy. E-mail: vdimarzo{at}icmib.na.cnr.it.

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 ß-cells.

Design, Setting, and Patients: Mouse 3T3-F442A adipocytes and rat insulinoma RIN-m5F ß-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 ß-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 ß-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 ß-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.

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