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

J Clin Endocrinol Metab. 2006 Aug;91(8):3171-80. doi: 10.1210/jc.2005-2679. Epub 2006 May 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adipocytes / chemistry*
  • Adipocytes / drug effects
  • Adiponectin / genetics
  • Adipose Tissue / chemistry
  • Adult
  • Animals
  • Cannabinoid Receptor Modulators / analysis
  • Cannabinoid Receptor Modulators / blood
  • Cannabinoid Receptor Modulators / physiology*
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / metabolism
  • Endocannabinoids*
  • Epididymis
  • Female
  • Gene Expression / drug effects
  • Glucose / pharmacology
  • Homeostasis
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / metabolism*
  • Insulin / pharmacology
  • Insulinoma
  • Intra-Abdominal Fat / chemistry
  • Islets of Langerhans / chemistry*
  • Islets of Langerhans / drug effects
  • Leptin / pharmacology
  • Male
  • Mice
  • Obesity / blood
  • Obesity / metabolism*
  • PPAR gamma / agonists
  • PPAR gamma / genetics
  • PPAR gamma / physiology
  • Pancreas / chemistry
  • Pancreatic Neoplasms
  • Rats
  • Signal Transduction / drug effects

Substances

  • Adiponectin
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Insulin
  • Leptin
  • PPAR gamma
  • Glucose