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

Background and Objectives: Cannabinoid-1 receptor signaling increases the rewarding effects of food intake and promotes the growth of adipocytes, whereas 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 oncannabimimetic signaling may become unbalanced with age because of alterations of the immune and endocannabinoid system.
Method: 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 in 12-16 week old mice.
Results: The CB2-/- mice were obese with hypertrophy of visceral fat, immune cell polarization towards pro-inflammatory sub-populations 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 towards the M1-like pro-inflammatory type and reduced HFD-evoked nociceptive hypersensitivity but had no effect on weight gain.
Conclusion: CB2 agonists may fortify CB2-mediated anti-obesity signaling without the risk of anti-CB1 mediated depression that caused the failure of rimonabant.International Journal of Obesity accepted article preview online, 25 August 2015. doi:10.1038/ijo.2015.169.