K Schmitz1, N Mangels2, A Häussler1, N Ferreirós1, I Fleming2, I Tegeder1,3. 1. Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany. 2. Institute for Vascular Signaling, Goethe-University Hospital, Frankfurt, Germany. 3. Fraunhofer Institute for Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt, Germany.
Abstract
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.
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.
Authors: Galina Burdyga; Andrea Varro; Rod Dimaline; David G Thompson; Graham J Dockray Journal: Am J Physiol Gastrointest Liver Physiol Date: 2010-04-29 Impact factor: 4.052
Authors: Douglas Osei-Hyiaman; Michael DePetrillo; Pál Pacher; Jie Liu; Svetlana Radaeva; Sándor Bátkai; Judith Harvey-White; Ken Mackie; László Offertáler; Lei Wang; George Kunos Journal: J Clin Invest Date: 2005-05 Impact factor: 14.808