title: CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.
abstract: The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice. Daily treatment with rimonabant for 14 days transiently reduced food intake in young and aged mice; however, the anorectic response was more profound in aged animals, coinciding with a substantive loss in body fat mass. Notably, reduced insulin sensitivity in aged skeletal muscle and liver concurred with increased CB1R mRNA abundance. Strikingly, rimonabant was shown to improve glucose tolerance and enhance skeletal muscle and liver insulin sensitivity in aged, but not young, adult mice. Moreover, rimonabant-mediated insulin sensitization in aged adipose tissue coincided with amelioration of low-grade inflammation and repressed lipogenic gene expression. Collectively, our findings indicate a key role for CB1R in aging-related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging.
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lipina
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Lobke M
authors.initials: LM
authors.lastname: Vaanholt
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Anastasija
authors.initials: A
authors.lastname: Davidova
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Mitchell
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Storey-Gordon
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Hambly
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital, University of Dundee, Dundee, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Irving
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.|Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China.
authors.forename: John R
authors.initials: JR
authors.lastname: Speakman
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Harinder S
authors.initials: HS
authors.lastname: Hundal
mesh_terms: D000367:Age Factors; D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002460:Cell Line; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D015870:Gene Expression; D007333:Insulin Resistance; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant
keywords: aging; cannabinoid receptor type 1; insulin resistance; rimonabant