Open AccessCB 1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction
Author(s) -
Lipina Christopher,
Vaanholt Lobke M.,
Davidova Anastasija,
Mitchell Sharon E.,
StoreyGordon Emma,
Hambly Catherine,
Irving Andrew J.,
Speakman John R.,
Hundal Harinder S.
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12438
Subject(s) - rimonabant , insulin resistance , endocrinology , medicine , endocannabinoid system , biology , metabolic syndrome , adipose tissue , cannabinoid receptor , inverse agonist , insulin , type 2 diabetes , insulin receptor , anorectic , skeletal muscle , blockade , agonist , receptor , diabetes mellitus , body weight
Summary 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 ( CB 1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB 1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57 BL /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 CB 1R 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 CB 1R in aging‐related insulin resistance and metabolic dysfunction and highlight CB 1R blockade as a potential strategy for combating metabolic disorders associated with aging.