Abstract
The purpose of the present study was to examine the effect of chronic exercise on the hypothalamus and hippocampus levels of the endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and of two AEA congeners and on the expression of genes coding for CB1, CB2 receptors (Cnr1 and Cnr2, respectively), and the enzymes responsible for eCB biosynthesis and degradation, in rats fed with a standard or high-fat diet. Male Wistar rats (n = 28) were placed on a 12-week high-fat (HFD) or standard diet period, followed by 12 weeks of exercise training for half of each group. Tissue levels of eCBs and related lipids were measured by liquid chromatography mass spectrometry, and expression of genes coding for CB1 and CB2 receptors and eCB metabolic enzymes was measured by quantitative real-time polymerase chain reaction (qPCR). HFD induced a significant increase in 2-AG (p < 0.01) in hypothalamus. High-fat diet paired with exercise training had no effect on AEA, 2-AG, and AEA congener levels in the hypothalamus and hippocampus. Cnr1 expression levels were significantly increased in the hippocampus in response to HFD, exercise, and the combination of both (p < 0.05). Our results indicate that eCB signaling in the CNS is sensitive to diet and/or exercise.
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05 October 2017
Volume 73 issue 3 was published with an incorrect cover date. Correct is August 2017. The Publisher apologizes for this mistake and all related inconveniences caused by this.
References
Artmann A, Petersen G, Hellgren LI, Boberg J, Skonberg C, Nellemann C, Hansen SH, Hansen HS (2008) Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta 1781:200–212
Baboota RK, Murtaza N, Jagtap S, Singh DP, Karmase A, Kaur J, Bhutani KK, Boparai RK, Premkumar LS, Kondepudi KK et al (2014) Capsaicin-induced transcriptional changes in hypothalamus and alterations in gut microbial count in high fat diet fed mice. J Nutr Biochem 25:893–902
Bennetzen MF (2011) Investigations of the endocannabinoid system in adipose tissue: effects of obesity/weight loss and treatment options. Dan Med Bull 58:B4269
Bisogno T, Mahadevan A, Coccurello R, Chang JW, Allara M, Chen Y, Giacovazzo G, Lichtman A, Cravatt B, Moles A et al (2013) A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects. Br J Pharmacol 169:784–793
Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356
Cadas H, Gaillet S, Beltramo M, Venance L, Piomelli D (1996) Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J Neurosci 16:3934–3942
Chalkley SM, Hettiarachchi M, Chisholm DJ, Kraegen EW (2002) Long-term high-fat feeding leads to severe insulin resistance but not diabetes in Wistar rats. Am J Physiol Endocrinol Metab 282:E1231–E1238
Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713
Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S et al (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431
Cristino L, Busetto G, Imperatore R, Ferrandino I, Palomba L, Silvestri C, Petrosino S, Orlando P, Bentivoglio M, Mackie K et al (2013) Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc Natl Acad Sci U S A 110:E2229–E2238
Cristino L, Luongo L, Imperatore R, Boccella S, Becker T, Morello G, Piscitelli F, Busetto G, Maione S, Di Marzo V (2016) Orexin-a and endocannabinoid activation of the descending antinociceptive pathway underlies altered pain perception in leptin signaling deficiency. Neuropsychopharmacology 41:508–520
D'Eon TM, Pierce KA, Roix JJ, Tyler A, Chen H, Teixeira SR (2008) The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids. Diabetes 57:1262–1268
De Chiara V, Errico F, Musella A, Rossi S, Mataluni G, Sacchetti L, Siracusano A, Castelli M, Cavasinni F, Bernardi G et al Voluntary exercise and sucrose consumption enhance cannabinoid CB1 receptor sensitivity in the striatum. Neuropsychopharmacology 35:374–387
Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T et al (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825
Di Marzo V, Matias I (2005) Endocannabinoid control of food intake and energy balance. Nat Neurosci 8:585–589
Di Marzo V (2008) Endocannabinoids: synthesis and degradation. Rev Physiol Biochem Pharmacol 160:1–24
Di Marzo V, Cote M, Matias I, Lemieux I, Arsenault BJ, Cartier A, Piscitelli F, Petrosino S, Almeras N, Despres JP (2009a) 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 52:213–217
Di Marzo V, Verrijken A, Hakkarainen A, Petrosino S, Mertens I, Lundbom N, Piscitelli F, Westerbacka J, Soro-Paavonen A, Matias I et al (2009b) Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects. Eur J Endocrinol 161:715–722
Dishman RK (1997) Brain monoamines, exercise, and behavioral stress: animal models. Med Sci Sports Exerc 29:63–74
Dubreucq S, Durand A, Matias I, Benard G, Richard E, Soria-Gomez E, Glangetas C, Groc L, Wadleigh A, Massa F et al (2013) Ventral tegmental area cannabinoid type-1 receptors control voluntary exercise performance. Biol Psychiatry 73:895–903
Gamelin FX, Aucouturier J, Iannotti FA, Piscitelli F, Mazzarella E, Aveta T, Leriche M, Dupont E, Cieniewski-Bernard C, Montel V, et al. (2016) Effects of chronic exercise on the endocannabinoid system in Wistar rats with high-fat diet-induced obesity. J Physiol Biochem
Harrold JA, Elliott JC, King PJ, Widdowson PS, Williams G (2002) Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food? Brain Res 952:232–238
Heyman E, Gamelin FX, Goekint M, Piscitelli F, Roelands B, Leclair E, Di Marzo V, Meeusen R (2012) Intense exercise increases circulating endocannabinoid and BDNF levels in humans—possible implications for reward and depression. Psychoneuroendocrinology 37:844–851
Hill MN, Patel S, Carrier EJ, Rademacher DJ, Ormerod BK, Hillard CJ, Gorzalka BB (2005) Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology 30:508–515
Hill MN, Titterness AK, Morrish AC, Carrier EJ, Lee TT, Gil-Mohapel J, Gorzalka BB, Hillard CJ, Christie BR (2010) Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20:513–523
Iannotti FA, Piscitelli F, Martella A, Mazzarella E, Allara M, Palmieri V, Parrella C, Capasso R, Di Marzo V (2013) Analysis of the "endocannabinoidome" in peripheral tissues of obese Zucker rats. Prostaglandins Leukot Essent Fatty Acids 89:127–135
Jamshidi N, Taylor DA (2001) Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 134:1151–1154
Jo YH, Chen YJ, Chua SC Jr, Talmage DA, Role LW (2005) Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron 48:1055–1066
Kim KW, Zhao L, Donato J Jr, Kohno D, Xu Y, Elias CF, Lee C, Parker KL, Elmquist JK (2011) Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc Natl Acad Sci U S A 108:10673–10678
Kirkham TC, Williams CM, Fezza F, Di Marzo V (2002) Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 136:550–557
Kirkham TC (2009) Endocannabinoids and the non-homeostatic control of appetite. Curr Top Behav Neurosci 1:231–253
Krawczewski Carhuatanta KA, Demuro G, Tschop MH, Pfluger PT, Benoit SC, Obici S (2011) Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity. Endocrinology 152:2655–2664
Liu YF, Chen HI, Wu CL, Kuo YM, Yu L, Huang AM, Wu FS, Chuang JI, Jen CJ (2009) Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I. J Physiol 587:3221–3231
Massa F, Mancini G, Schmidt H, Steindel F, Mackie K, Angioni C, Oliet SH, Geisslinger G, Lutz B (2010) Alterations in the hippocampal endocannabinoid system in diet-induced obese mice. J Neurosci 30:6273–6281
Matias I, Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V (2008) Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: effect of high fat diets. Mol Cell Endocrinol 286:S66–S78
Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (2006) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27:73–100
Pedersen BK, Saltin B (2006) Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports 16(Suppl 1):3–63
Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J & Group RI-NAS (2006) Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295:761–775
Purves RD (1992) Optimum numerical integration methods for estimation of area-under-the-curve (AUC) and area-under-the-moment-curve (AUMC). J Pharmacokinet Biopharm 20:211–226
Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012) Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high. J Exp Biol 215:1331–1336
Rivera P, Luque-Rojas MJ, Pastor A, Blanco E, Pavon FJ, Serrano A, Crespillo A, Vida M, Grondona JM, Cifuentes M et al (2013) Diet-dependent modulation of hippocampal expression of endocannabinoid signaling-related proteins in cannabinoid antagonist-treated obese rats. Eur J Neurosci 37:105–117
Senst L, Bains J (2014) Neuromodulators, stress and plasticity: a role for endocannabinoid signalling. J Exp Biol 217:102–108
Silvestri C, Di Marzo V (2013) The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab 17:475–490
South T, Huang XF (2008) Temporal and site-specific brain alterations in CB1 receptor binding in high fat diet-induced obesity in C57Bl/6 mice. J Neuroendocrinol 20:1288–1294
Sparling PB, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A (2003) Exercise activates the endocannabinoid system. Neuroreport 14:2209–2211
Stranahan AM, Lee K, Mattson MP (2008) Central mechanisms of HPA axis regulation by voluntary exercise. NeuroMolecular Med 10:118–127
Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014) Physical activity and the endocannabinoid system: an overview. Cell Mol Life Sci 71:2681–2698
van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685
Verty AN, McGregor IS, Mallet PE (2004) The dopamine receptor antagonist SCH 23390 attenuates feeding induced by Delta9-tetrahydrocannabinol. Brain Res 1020:188–195
Wamsteeker JI, Kuzmiski JB, Bains JS (2010) Repeated stress impairs endocannabinoid signaling in the paraventricular nucleus of the hypothalamus. J Neurosci 30:11188–11196
Yan ZC, Liu DY, Zhang LL, Shen CY, Ma QL, Cao TB, Wang LJ, Nie H, Zidek W, Tepel M et al (2007) Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta. Biochem Biophys Res Commun 354:427–433
Zsombok A (2013) Vanilloid receptors—do they have a role in whole body metabolism? Evidence from TRPV1. J Diabetes Complicat 27:287–292
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The authors thank Gamain J., Barbez P., Max, and Mahault G. for their advices and technical assistances.
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Vincenzo Di Marzo, and Elsa Heyman share the senior authorship.
An erratum to this article is available at https://doi.org/10.1007/s13105-017-0593-x.
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Gamelin, FX., Aucouturier, J., Iannotti, F.A. et al. Exercise training and high-fat diet elicit endocannabinoid system modifications in the rat hypothalamus and hippocampus. J Physiol Biochem 73, 335–347 (2016). https://doi.org/10.1007/s13105-017-0557-1
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DOI: https://doi.org/10.1007/s13105-017-0557-1