title: Cannabinoid receptor 1 (CB1) antagonism enhances glucose utilisation and activates brown adipose tissue in diet-induced obese mice.
abstract: OBJECTIVE
  We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function.
  
  
  METHODS
  Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.
  
  
  RESULTS
  Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake.
  
  
  CONCLUSIONS
  Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.
authors: Metabolic Diseases Institute, University of Cincinnati, 2140 East Galbraith Road, Building B, Room 332, Cincinnati, OH 45237-1625, USA.
authors: M
authors: M
authors: Bajzer
authors: M
authors: M
authors: Olivieri
authors: M K
authors: MK
authors: Haas
authors: P T
authors: PT
authors: Pfluger
authors: I J
authors: IJ
authors: Magrisso
authors: M T
authors: MT
authors: Foster
authors: M H
authors: MH
authors: Tschöp
authors: K A
authors: KA
authors: Krawczewski-Carhuatanta
authors: D
authors: D
authors: Cota
authors: S
authors: S
authors: Obici
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000294:innervation / Q000378:metabolism* / Q000601:surgery; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D022722:Thermogenesis / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
chemical_list: D007328:Insulin; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D006003:Glycogen; D005947:Glucose; D000077285:Rimonabant