PMID- 21799481
OWN - NLM
STAT- MEDLINE
DCOM- 20120327
LR  - 20181201
IS  - 1930-739X (Electronic)
IS  - 1930-7381 (Linking)
VI  - 19
IP  - 10
DP  - 2011 Oct
TI  - The central cannabinoid CB1 receptor is required for diet-induced obesity and 
      rimonabant's antiobesity effects in mice.
PG  - 1923-34
LID - 10.1038/oby.2011.250 [doi]
AB  - 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.
FAU - Pang, Zhen
AU  - Pang Z
AD  - Department of Biological Sciences, Sanofi-Aventis US Inc., Bridgewater, New 
      Jersey, USA. zhen.pang@sanofi-aventis.com
FAU - Wu, Nancy N
AU  - Wu NN
FAU - Zhao, Weiguang
AU  - Zhao W
FAU - Chain, David C
AU  - Chain DC
FAU - Schaffer, Erica
AU  - Schaffer E
FAU - Zhang, Xin
AU  - Zhang X
FAU - Yamdagni, Preeti
AU  - Yamdagni P
FAU - Palejwala, Vaseem A
AU  - Palejwala VA
FAU - Fan, Chunpeng
AU  - Fan C
FAU - Favara, Sarah G
AU  - Favara SG
FAU - Dressler, Holly M
AU  - Dressler HM
FAU - Economides, Kyriakos D
AU  - Economides KD
FAU - Weinstock, Daniel
AU  - Weinstock D
FAU - Cavallo, Jean S
AU  - Cavallo JS
FAU - Naimi, Souad
AU  - Naimi S
FAU - Galzin, Anne-Marie
AU  - Galzin AM
FAU - Guillot, Etienne
AU  - Guillot E
FAU - Pruniaux, Marie-Pierre
AU  - Pruniaux MP
FAU - Tocci, Michael J
AU  - Tocci MJ
FAU - Polites, H Greg
AU  - Polites HG
LA  - eng
PT  - Journal Article
DEP - 20110728
PL  - United States
TA  - Obesity (Silver Spring)
JT  - Obesity (Silver Spring, Md.)
JID - 101264860
RN  - 0 (Adiponectin)
RN  - 0 (Anti-Obesity Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Insulin)
RN  - 0 (Leptin)
RN  - 0 (MicroRNAs)
RN  - 0 (Piperidines)
RN  - 0 (Pyrazoles)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 0 (Triglycerides)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - RML78EN3XE (Rimonabant)
SB  - IM
MH  - Adiponectin/blood
MH  - Adiposity/drug effects/genetics
MH  - Animals
MH  - Anti-Obesity Agents/*pharmacology/therapeutic use
MH  - Biomarkers/blood
MH  - Body Weight/*drug effects/genetics
MH  - Central Nervous System/drug effects/*metabolism
MH  - Cholesterol/blood
MH  - Diet, High-Fat/adverse effects
MH  - Energy Intake/*drug effects/genetics
MH  - Gastrointestinal Transit/physiology
MH  - Hypothermia/prevention & control
MH  - Insulin/blood
MH  - Leptin/blood
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - MicroRNAs
MH  - Mutation
MH  - Obesity/drug therapy/genetics/*metabolism
MH  - Peripheral Nervous System/drug effects/metabolism
MH  - Phenotype
MH  - Piperidines/*pharmacology/therapeutic use
MH  - Promoter Regions, Genetic
MH  - Pyrazoles/*pharmacology/therapeutic use
MH  - Receptor, Cannabinoid, CB1/genetics/*metabolism
MH  - Rimonabant
MH  - Triglycerides/blood
EDAT- 2011/07/30 06:00
MHDA- 2012/03/28 06:00
CRDT- 2011/07/30 06:00
PHST- 2011/07/30 06:00 [entrez]
PHST- 2011/07/30 06:00 [pubmed]
PHST- 2012/03/28 06:00 [medline]
AID - oby2011250 [pii]
AID - 10.1038/oby.2011.250 [doi]
PST - ppublish
SO  - Obesity (Silver Spring). 2011 Oct;19(10):1923-34. doi: 10.1038/oby.2011.250. Epub 
      2011 Jul 28.