CONTEXT: 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. DESIGN, SETTING, AND PATIENTS: 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. 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 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.
CONTEXT: 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. DESIGN, SETTING, AND PATIENTS: Mouse 3T3-F442A adipocytes and ratinsulinoma 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 diabetespatients 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 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.
Authors: Mónica Alonso; Antonia Serrano; Margarita Vida; Ana Crespillo; Laura Hernandez-Folgado; Nadine Jagerovic; Pilar Goya; Carmen Reyes-Cabello; Vidal Perez-Valero; Juan Decara; Manuel Macías-González; Francisco Javier Bermúdez-Silva; Juan Suárez; Fernando Rodríguez de Fonseca; Francisco Javier Pavón Journal: Br J Pharmacol Date: 2012-04 Impact factor: 8.739
Authors: R G Pertwee; A C Howlett; M E Abood; S P H Alexander; V Di Marzo; M R Elphick; P J Greasley; H S Hansen; G Kunos; K Mackie; R Mechoulam; R A Ross Journal: Pharmacol Rev Date: 2010-12 Impact factor: 25.468
Authors: Katarzyna Malenczyk; Fatima Girach; Edit Szodorai; Petter Storm; Åsa Segerstolpe; Giuseppe Tortoriello; Robert Schnell; Jan Mulder; Roman A Romanov; Erzsébet Borók; Fabiana Piscitelli; Vincenzo Di Marzo; Gábor Szabó; Rickard Sandberg; Stefan Kubicek; Gert Lubec; Tomas Hökfelt; Ludwig Wagner; Leif Groop; Tibor Harkany Journal: EMBO J Date: 2017-06-21 Impact factor: 11.598