title: Pro-inflammatory obesity in aged cannabinoid-2 receptor-deficient mice.
abstract: OBJECTIVE
  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.
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors: K
authors: K
authors: Schmitz
authors: Institute for Vascular Signaling, Goethe-University Hospital, Frankfurt, Germany.
authors: N
authors: N
authors: Mangels
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors: A
authors: A
authors: Häussler
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors: N
authors: N
authors: Ferreirós
authors: Institute for Vascular Signaling, Goethe-University Hospital, Frankfurt, Germany.
authors: I
authors: I
authors: Fleming
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt, Germany.
authors: I
authors: I
authors: Tegeder
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002186:Cannabinoids; D043885:Receptor, Cannabinoid, CB2