title: Central endocannabinoid signaling regulates hepatic glucose production and systemic lipolysis.
abstract: OBJECTIVE
  The endocannabinoid (EC) system has been implicated as an important regulator of energy homeostasis. In obesity and type 2 diabetes, EC tone is elevated in peripheral tissues including liver, muscle, fat, and also centrally, particularly in the hypothalamus. Cannabinoid receptor type 1 (CB₁) blockade with the centrally and peripherally acting rimonabant induces weight loss and improves glucose homeostasis while also causing psychiatric adverse effects. The relative contributions of peripheral versus central EC signaling on glucose homeostasis remain to be elucidated. The aim of this study was to test whether the central EC system regulates systemic glucose fluxes.
  
  
  METHODS
  We determined glucose and lipid fluxes in male Sprague-Dawley rats during intracerebroventricular infusions of either WIN55,212-2 (WIN) or arachidonoyl-2'-chloroethylamide (ACEA) while controlling circulating insulin and glucose levels through hyperinsulinemic, euglycemic clamp studies. Conversely, we fed rats a high-fat diet for 3 days and then blocked central EC signaling with an intracerebroventricular infusion of rimonabant while assessing glucose fluxes during a clamp.
  
  
  RESULTS
  Central CB₁ activation is sufficient to impair glucose homeostasis. Either WIN or ACEA infusions acutely impaired insulin action in both liver and adipose tissue. Conversely, in a model of overfeeding-induced insulin resistance, CB₁ antagonism restored hepatic insulin sensitivity.
  
  
  CONCLUSIONS
  Thus central EC tone plays an important role in regulating hepatic and adipose tissue insulin action. These results indicate that peripherally restricted CB₁ antagonists, which may lack psychiatric side effects, are also likely to be less effective than brain-permeable CB₁ antagonists in ameliorating insulin resistance.
authors: Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA. christoph.buettner@mssm.edu
authors: James D
authors: JD
authors: O'Hare
authors: Elizabeth
authors: E
authors: Zielinski
authors: Bob
authors: B
authors: Cheng
authors: Thomas
authors: T
authors: Scherer
authors: Christoph
authors: C
authors: Buettner
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D063388:Endocannabinoids; D005947:Glucose / Q000378:metabolism*; D057967:Infusions, Intraventricular; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C119325:arachidonyl-2-chloroethylamide; D005947:Glucose; D000077285:Rimonabant