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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Williams CM, Kirkham TC . Observational analysis of feeding induced by Delta9-THC and anandamide. Physiol Behav 2002; 76: 241–250.
Osei-Hyiaman D, Harvey-White J, Batkai S, Kunos G . The role of the endocannabinoid system in the control of energy homeostasis. Int J Obes 2006; 30: S33–S38.
Jamshidi N, Taylor DA . Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 2001; 134: 1151–1154.
Di Marzo V, Cote M, Matias I, Lemieux I, Arsenault BJ, Cartier A et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia 2009; 52: 213–217.
Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Batkai S et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 2006; 55: 3053–3060.
Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 2002; 22: 9612–9617.
Burdyga G, Varro A, Dimaline R, Thompson DG, Dockray GJ . Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype. Am J Physiol Gastrointest Liver Physiol 2010; 299: G63–G69.
Bellocchio L, Lafenetre P, Cannich A, Cota D, Puente N, Grandes P et al. Bimodal control of stimulated food intake by the endocannabinoid system. Nat Neurosci 2010; 13: 281–283.
Cardinal P, Bellocchio L, Clark S, Cannich A, Klugmann M, Lutz B et al. Hypothalamic CB1 cannabinoid receptors regulate energy balance in mice. Endocrinology 2012; 153: 4136–4143.
Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410: 822–825.
Cota D . CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Diabetes Metab Res Rev 2007; 23: 507–517.
Cota D, Sandoval DA, Olivieri M, Prodi E, D'Alessio DA, Woods SC et al. Food intake-independent effects of CB1 antagonism on glucose and lipid metabolism. Obesity (Silver Spring) 2009; 17: 1641–1645.
Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115: 1298–1305.
Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI et al. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 2008; 118: 3160–3169.
Di Marzo V, Despres JP . CB1 antagonists for obesity—what lessons have we learned from rimonabant? Nat Rev Endocrinol 2009; 5: 633–638.
Son MH, Kim HD, Chae YN, Kim MK, Shin CY, Ahn GJ et al. Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control. Int J Obes 2010; 34: 547–556.
Bell-Anderson KS, Aouad L, Williams H, Sanz FR, Phuyal J, Larter CZ et al. Coordinated improvement in glucose tolerance, liver steatosis and obesity-associated inflammation by cannabinoid 1 receptor antagonism in fat Aussie mice. Int J Obes 2011; 35: 1539–1548.
Bergholm R, Sevastianova K, Santos A, Kotronen A, Urjansson M, Hakkarainen A et al. CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans. Int J Obes 2013; 37: 699–703.
Koolman AH, Bloks VW, Oosterveer MH, Jonas I, Kuipers F, Sauer PJ et al. Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition. Int J Obes 2010; 34: 374–384.
Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P . CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 2004; 28: 640–648.
Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003; 112: 423–431.
Rayman N, Lam KH, Van Leeuwen J, Mulder AH, Budel LM, Lowenberg B et al. The expression of the peripheral cannabinoid receptor on cells of the immune system and non-Hodgkin's lymphomas. Leuk Lymphoma 2007; 48: 1389–1399.
Romero-Sandoval EA, Horvath R, Landry RP, DeLeo JA . Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol Pain 2009; 5: 25.
Nunez E, Benito C, Pazos MR, Barbachano A, Fajardo O, Gonzalez S et al. Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 2004; 53: 208–213.
Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA et al. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann NY Acad Sci 2006; 1074: 514–536.
Correa F, Mestre L, Docagne F, Guaza C . Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages: role of IL-10 and ERK1/2 kinase signaling. Br J Pharmacol 2005; 145: 441–448.
Defer N, Wan J, Souktani R, Escoubet B, Perier M, Caramelle P et al. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. FASEB J 2009; 23: 2120–2130.
Singh UP, Singh NP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS . Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol 2012; 258: 256–267.
Oka S, Wakui J, Ikeda S, Yanagimoto S, Kishimoto S, Gokoh M et al. Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice. J Immunol 2006; 177: 8796–8805.
Akhmetshina A, Dees C, Busch N, Beer J, Sarter K, Zwerina J et al. The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis Rheum 2009; 60: 1129–1136.
Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 2005; 102: 3093–3098.
Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci USA 2003; 100: 10529–10533.
Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 2014; 20: 614–625.
Hill AA, Reid Bolus W, Hasty AH . A decade of progress in adipose tissue macrophage biology. Immunol Rev 2014; 262: 134–152.
Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 2009; 58: 2574–2582.
Lumeng CN, Bodzin JL, Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 175–184.
Romero-Zerbo SY, Garcia-Gutierrez MS, Suarez J, Rivera P, Ruz-Maldonado I, Vida M et al. Overexpression of cannabinoid CB2 receptor in the brain induces hyperglycaemia and a lean phenotype in adult mice. J Neuroendocrinol 2012; 24: 1106–1119.
Agudo J, Martin M, Roca C, Molas M, Bura AS, Zimmer A et al. Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age. Diabetologia 2010; 53: 2629–2640.
Garg SK, Delaney C, Shi H, Yung R . Changes in adipose tissue macrophages and T cells during aging. Crit Rev Immunol 2014; 34: 1–14.
Bishay P, Haussler A, Lim HY, Oertel B, Galve-Roperh I, Ferreiros N et al. Anandamide deficiency and heightened neuropathic pain in aged mice. Neuropharmacology 2013; 71: 204–215.
Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M et al. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 1999; 96: 14228–14233.
Sagredo O, Gonzalez S, Aroyo I, Pazos MR, Benito C, Lastres-Becker I et al. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington's disease. Glia 2009; 57: 1154–1167.
Bishay P, Schmidt H, Marian C, Haussler A, Wijnvoord N, Ziebell S et al. R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids. PLoS One 2010; 5: e10628.
Ferreiros N, Labocha S, Walter C, Lotsch J, Geisslinger G . Simultaneous and sensitive LC-MS/MS determination of tetrahydrocannabinol and metabolites in human plasma. Anal Bioanal Chem 2013; 405: 1399–1406.
Kanngiesser M, Mair N, Lim HY, Zschiebsch K, Blees J, Haussler A et al. Hypoxia-inducible factor 1 regulates heat and cold pain sensitivity and persistence. Antioxid Redox Signal 2014; 20: 2555–2571.
Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 2006; 3: 167–175.
Schwartz GJ, Fu J, Astarita G, Li X, Gaetani S, Campolongo P et al. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab 2008; 8: 281–288.
Alen F, Crespo I, Ramirez-Lopez MT, Jagerovic N, Goya P, de Fonseca FR et al. Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism. PLoS One 2013; 8: e60918.
Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 2010; 59: 347–357.
Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010; 59: 1648–1656.
Wang S, Davis BM, Zwick M, Waxman SG, Albers KM . Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice. Neurobiol Aging 2006; 27: 895–903.
Ribas V, Drew BG, Le JA, Soleymani T, Daraei P, Sitz D et al. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci USA 2011; 108: 16457–16462.
Chadwick CC, Chippari S, Matelan E, Borges-Marcucci L, Eckert AM, Keith JC Jr. et al. Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity. Proc Natl Acad Sci USA 2005; 102: 2543–2548.
Finan B, Yang B, Ottaway N, Stemmer K, Muller TD, Yi CX et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med 2012; 18: 1847–1856.
Barros RP, Gustafsson JA . Estrogen receptors and the metabolic network. Cell Metab 2011; 14: 289–299.
Johnson AM, Olefsky JM . The origins and drivers of insulin resistance. Cell 2013; 152: 673–684.
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA 2014; 111: 16136–16141.
Rohleder N, Aringer M, Boentert M . Role of interleukin-6 in stress, sleep, and fatigue. Ann NY Acad Sci 2012; 1261: 88–96.
Hong S, Wiley JW . Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem 2005; 280: 618–627.
Kramer HH, Rolke R, Bickel A, Birklein F . Thermal thresholds predict painfulness of diabetic neuropathies. Diabetes Care 2004; 27: 2386–2391.
Vlckova-Moravcova E, Bednarik J, Belobradkova J, Sommer C . Small-fibre involvement in diabetic patients with neuropathic foot pain. Diabet Med 2008; 25: 692–699.
Sorensen L, Molyneaux L, Yue DK . The level of small nerve fiber dysfunction does not predict pain in diabetic Neuropathy: a study using quantitative sensory testing. Clin J Pain 2006; 22: 261–265.
Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S et al. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS One 2009; 4: e5844.
Verty AN, Lockie SH, Stefanidis A, Oldfield BJ . Anti-obesity effects of the combined administration of CB1 receptor antagonist rimonabant and melanin-concentrating hormone antagonist SNAP-94847 in diet-induced obese mice. Int J Obes 2013; 37: 279–287.
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on International Journal of Obesity website
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ijo.2015.169
This article is cited by
-
Hypothalamic endocannabinoids in obesity: an old story with new challenges
Cellular and Molecular Life Sciences (2021)
-
The endocannabinoid system in cardiovascular function: novel insights and clinical implications
Clinical Autonomic Research (2018)