Pro-inflammatory obesity in aged cannabinoid-2 receptor-deficient mice

Int J Obes (Lond). 2016 Feb;40(2):366-79. doi: 10.1038/ijo.2015.169. Epub 2015 Aug 25.


Background and objectives: Cannabinoid-1 receptor signaling increases the rewarding effects of food intake and promotes the growth of adipocytes, whereas cannabinoid-2 receptor (CB2) possibly opposes these pro-obesity effects by silencing the activated immune cells that are key drivers of the metabolic syndrome. Pro- and anti-orexigenic cannabimimetic signaling may become unbalanced with age because of alterations of the immune and endocannabinoid system.

Methods: To specifically address the role of CB2 for age-associated obesity, we analyzed metabolic, cardiovascular, immune and neuronal functions in 1.2-1.8-year-old CB2(-/-) and control mice, fed with a standard diet and assessed effects of the CB2 agonist, HU308, during high-fat diet (HFD) in 12-16-week-old mice.

Results: The CB2(-/-) mice were obese with hypertrophy of visceral fat, immune cell polarization toward pro-inflammatory subpopulations in fat and liver and hypertension, as well as increased mortality despite normal blood glucose. They also developed stronger paw inflammation and a premature loss of transient receptor potential responsiveness in primary sensory neurons, a phenomenon typical for small fiber disease. The CB2 agonist HU308 prevented HFD-evoked hypertension, reduced HFD-evoked polarization of adipose tissue macrophages toward the M1-like pro-inflammatory type and reduced HFD-evoked nociceptive hypersensitivity, but had no effect on weight gain.

Conclusions: CB2 agonists may fortify CB2-mediated anti-obesity signaling without the risk of anti-CB1-mediated depression that caused the failure of rimonabant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Animals
  • Cannabinoids / pharmacology*
  • Diet, High-Fat
  • Disease Models, Animal
  • Inflammation / metabolism
  • Intra-Abdominal Fat / metabolism
  • Intra-Abdominal Fat / pathology*
  • Mice
  • Mice, Knockout
  • Obesity / metabolism*
  • Receptor, Cannabinoid, CB2 / deficiency
  • Receptor, Cannabinoid, CB2 / metabolism*


  • Cannabinoids
  • Receptor, Cannabinoid, CB2