title: The central cannabinoid CB1 receptor is required for diet-induced obesity and rimonabant's antiobesity effects in mice.
abstract: Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions.
authors.affiliation: Department of Biological Sciences, Sanofi-Aventis US Inc., Bridgewater, New Jersey, USA. zhen.pang@sanofi-aventis.com
authors.forename: Zhen
authors.initials: Z
authors.lastname: Pang
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Wu
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zhao
authors.forename: David C
authors.initials: DC
authors.lastname: Chain
authors.forename: Erica
authors.initials: E
authors.lastname: Schaffer
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Preeti
authors.initials: P
authors.lastname: Yamdagni
authors.forename: Vaseem A
authors.initials: VA
authors.lastname: Palejwala
authors.forename: Chunpeng
authors.initials: C
authors.lastname: Fan
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Favara
authors.forename: Holly M
authors.initials: HM
authors.lastname: Dressler
authors.forename: Kyriakos D
authors.initials: KD
authors.lastname: Economides
authors.forename: Daniel
authors.initials: D
authors.lastname: Weinstock
authors.forename: Jean S
authors.initials: JS
authors.lastname: Cavallo
authors.forename: Souad
authors.initials: S
authors.lastname: Naimi
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Galzin
authors.forename: Etienne
authors.initials: E
authors.lastname: Guillot
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Pruniaux
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tocci
authors.forename: H Greg
authors.initials: HG
authors.lastname: Polites
mesh_terms: D052242:Adiponectin / Q000097:blood; D050154:Adiposity / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001835:Body Weight / Q000187:drug effects* / Q000235:genetics; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D002149:Energy Intake / Q000187:drug effects* / Q000235:genetics; D005772:Gastrointestinal Transit / Q000502:physiology; D007035:Hypothermia / Q000517:prevention & control; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs; D009154:Mutation; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D014280:Triglycerides / Q000097:blood
chemical_list: D052242:Adiponectin; D019440:Anti-Obesity Agents; D015415:Biomarkers; D007328:Insulin; D020738:Leptin; D035683:MicroRNAs; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014280:Triglycerides; D002784:Cholesterol; D000077285:Rimonabant