CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction

Christopher Lipina, Lobke M. Vaanholt, Anastasija Davidova, Sharon E. Mitchell, Emma Storey-Gordon, Catherine Hambly, Andrew J. Irving, John R. Speakman, Harinder S. (Hari) Hundal (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)325-335
Number of pages11
JournalAging Cell
Volume15
Issue number2
Early online date13 Jan 2016
DOIs
Publication statusPublished - Apr 2016

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rimonabant
Cannabinoid Receptor CB1
Cannabinoid Receptors
Insulin Resistance
Adipose Tissue
Skeletal Muscle
Appetite Depressants
Endocannabinoids
Liver
Feeding Behavior
Inbred C57BL Mouse
Young Adult
Homeostasis
Obesity
Eating
Insulin
Inflammation
Gene Expression
Glucose
Messenger RNA

Keywords

  • Aging
  • Cannabinoid receptor type 1
  • Insulin resistance
  • Rimonabant

Cite this

Lipina, Christopher ; Vaanholt, Lobke M. ; Davidova, Anastasija ; Mitchell, Sharon E. ; Storey-Gordon, Emma ; Hambly, Catherine ; Irving, Andrew J. ; Speakman, John R. ; Hundal, Harinder S. (Hari). / CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction. In: Aging Cell. 2016 ; Vol. 15, No. 2. pp. 325-335.
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Lipina, C, Vaanholt, LM, Davidova, A, Mitchell, SE, Storey-Gordon, E, Hambly, C, Irving, AJ, Speakman, JR & Hundal, HSH 2016, 'CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction', Aging Cell, vol. 15, no. 2, pp. 325-335. https://doi.org/10.1111/acel.12438

CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction. / Lipina, Christopher; Vaanholt, Lobke M.; Davidova, Anastasija; Mitchell, Sharon E.; Storey-Gordon, Emma; Hambly, Catherine; Irving, Andrew J.; Speakman, John R.; Hundal, Harinder S. (Hari) (Lead / Corresponding author).

In: Aging Cell, Vol. 15, No. 2, 04.2016, p. 325-335.

Research output: Contribution to journalArticle

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AU - Hambly, Catherine

AU - Irving, Andrew J.

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Lipina C, Vaanholt LM, Davidova A, Mitchell SE, Storey-Gordon E, Hambly C et al. CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction. Aging Cell. 2016 Apr;15(2):325-335. https://doi.org/10.1111/acel.12438