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.
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.
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.
CB2 agonists may fortify CB2-mediated anti-obesity signaling without the risk of anti-CB1-mediated depression that caused the failure of rimonabant.
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We acknowledge the financial support of the Deutsche Forschungsgemeinschaft (CRC1039 A03 to IT, and Z1) and the Else Kröner Fresenius Foundation (Translational Research Innovation Pharma (TRIP) graduate school, scholar KS). We thank Sandra Labocha and Yannick Schreiber for technical assistance.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on International Journal of Obesity website
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Schmitz, K., Mangels, N., Häussler, A. et al. Pro-inflammatory obesity in aged cannabinoid-2 receptor-deficient mice. Int J Obes 40, 366–379 (2016). https://doi.org/10.1038/ijo.2015.169
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