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.