title: A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis.
abstract: OBJECTIVE
  To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice.
  
  
  METHODS
  The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined.
  
  
  RESULTS
  Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in β-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the β2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice.
  
  
  CONCLUSIONS
  BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors: W-C
authors: WC
authors: Hsiao
authors: K-S
authors: KS
authors: Shia
authors: Y-T
authors: YT
authors: Wang
authors: Y-N
authors: YN
authors: Yeh
authors: C-P
authors: CP
authors: Chang
authors: Y
authors: Y
authors: Lin
authors: P-H
authors: PH
authors: Chen
authors: C-H
authors: CH
authors: Wu
authors: Y-S
authors: YS
authors: Chao
authors: M-S
authors: MS
authors: Hung
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000188:drug therapy / Q000209:etiology; D007473:Ion Channels / Q000235:genetics; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics; D009765:Obesity / Q000150:complications / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D022722:Thermogenesis / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*; D000071256:Uncoupling Protein 1; D015431:Weight Loss / Q000187:drug effects*
chemical_list: C554616:1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide; D019440:Anti-Obesity Agents; D063387:Cannabinoid Receptor Antagonists; D007473:Ion Channels; D024101:Mitochondrial Proteins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013876:Thiophenes; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000077285:Rimonabant
keywords: food intake; metabolic disorders; obesity; peripheral CB1R antagonist; thermogenesis; β2-adrenoceptor