Dyaglicerol Lipase (DAGL) is the enzyme responsible of the biosynthesis of the endocannabinoid 2-AG. DAGL has been proposed as a target to treat diseases as Alzheimer's, Metabolic Disorders and Addictions.

Chemical Name: 
Diacylglycerol lipase
Wikipedia entry: 
Receptors: 
Endocannabinoids: 
Literature Discussion: 

DAGL is responsible for the biosynthesis of 2-AG (Biernacki & Skrzydlewska, 2016).

DAGLα is usually expressed on postsynaptic neurons, with higher presence in the cerebellum (Baggelaar et al., 2017), while DAGLβ is usually expressed on microglia and macrophages. DAGL also participates in oligodendrocyte differentiation (Gomez et al., 2010).

Zebrafish DAGLα knockdown experiments showed that 2-AG modulates axon formation in the midbrain and hindbrain areas, suggesting its implication in the control of vision and movement (Martella et al., 2016).

Inhibition of DAGL reduced the movement of neuroblasts in the rostral migratory steam and when these were moving, they moved in random directions. This effect was mediated by 2-AG and CB1 receptors and has important implications for the understanding of CNS development (Oudin, Gajendra, et al., 2011; Zhou et al., 2015).

Nox-induced oxyradical stress elicited the activation of DAGLβ in vitro, increasing the biosynthesis of 2-AG (Matthews et al., 2016). DAGLβ modulates pro-inflammatory signaling cascades and its inhibition reduced nociceptive behavior in models of neuropathic and inflammatory pain (Wilkerson et al., 2016).

DAGL modulates brain lipid transmitters like endocannabinoids, eicosanoids and diacylglycerols. This lipid signaling modulates synaptic plasticity, neuroinflammation and behaviors related to pain, emotions and addictions (Ogasawara et al., 2016). Inhibition of DAGL reduces 2-AG levels as well as synaptic plasticity in the hippocampus of mice, suggesting that on-demand 2-AG biosynthesis modulates retrograde signaling (Baggelaar et al., 2015). DAGL has been associated with synaptic plasticity and retrograde signaling in several studies (Gao et al., 2010; Marinelli et al., 2008; Oudin, Hobbs, & Doherty, 2011; Yoshino et al., 2011).

DAGL increased lifespan and reduced oxidative stress in Drosophila and C. elegans through TOR modulation (Lin et al., 2014). DAGL modulation has been also linked to age processes in other studies (Gaveglio, Pascual, Giusto, & Pasquaré, 2016; Goncalves et al., 2008; Pascual, Gaveglio, Giusto, & Pasquaré, 2014, 2013; Pasquaré, Gaveglio, & Giusto, 2009)

Nicotine exposure in rats increased 2-AG biosynthesis in the ventral tegmental area (VTA). 2-AG reduces GABA signaling, increasing VTA sensitivity to nicotine and increasing sensitization of DA release in the nucleus accumbens. Inhibition of DAGL restored GABA signaling in the VTA, making DAGL an interesting target to treat addictions (Buczynski et al., 2016). Following the same line, morphine withdrawal increased DAGLα expression in rat nucleus accumbens and increased depolarization-induced suppression of inhibition, suggesting that 2-AG mediates this process (Wang et al., 2016). Furthermore, a study testing the effects of cocaine in orexin neurons found very similar results (Tung et al., 2016).

DAGL inhibitors have been proposed to treat metabolic disorders due to their effects on the CB1 receptor through 2-AG (Janssen & van der Stelt, 2016). DAGL inhibitors can avoid fasting-induced refeeding of mice, showing a similar pharmacokinetic profile to CB1 inverse agonists (Deng et al., 2017). There are other studies linking DAGL and 2-AG activity with eating disorders (Bisogno et al., 2013; Engeli et al., 2014). Also, DAGL inhibition reverts the effects on food intake and rapid eye movement sleep in rats caused by the stimulation protease activated receptor 1 (PPAR-1) in the lateral hypothalamus. This suggest synergistic actions between PAR1 and 2-AG (Pérez-Morales, Fajardo-Valdez, Méndez-Díaz, Ruiz-Contreras, & Prospéro-García, 2014).

DAGL and NAPE are downregulated while MAGL and FAAH are upregulated in subjects who had a first episode of psychosis (Bioque et al., 2013).

DAGLα is expressed in the enteric nervous system including the gastrointestinal tract. Genetically constipated mice and CB1 deficient mice reversed their symptoms of slow gastrointestinal motility, intestinal contractility and constipation after DAGLα inhibition. These effects were mediated by 2-AG and CB1 receptors (Bashashati et al., 2015).

DAGLα knockout mice showed a reduction of 80% of 2-AG, reduction of AEA and increased fear and Anxiety responses (Jenniches et al., 2016).

DAGL decreased its activity under the presence of Aβ1-40 oligomers, leading to lower levels of 2-AG, which could be associated to AD progression (Pascual, Gaveglio, Giusto, & Pasquaré, 2017).

References:

Baggelaar, M. P., Chameau, P. J. P., Kantae, V., Hummel, J., Hsu, K.-L., Janssen, F., … van der Stelt, M. (2015). Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons. Journal of the American Chemical Society, 137(27), 8851-8857. https://doi.org/10.1021/jacs.5b04883

Baggelaar, M. P., van Esbroeck, A. C. M., van Rooden, E. J., Florea, B. I., Overkleeft, H. S., Marsicano, G., … van der Stelt, M. (2017). Chemical Proteomics Maps Brain Region Specific Activity of endocannabinoid Hydrolases. ACS Chemical Biology, 12(3), 852-861. https://doi.org/10.1021/acschembio.6b01052

Bashashati, M., Nasser, Y., Keenan, C. M., Ho, W., Piscitelli, F., Nalli, M., … Sharkey, K. A. (2015). Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. British Journal of Pharmacology, 172(12), 3099-3111. https://doi.org/10.1111/bph.13114

Biernacki, M., & Skrzydlewska, E. (2016). Metabolism of endocannabinoids. Postepy Higieny I Medycyny Doswiadczalnej (Online), 70(0), 830-843.

Bioque, M., García-Bueno, B., Macdowell, K. S., Meseguer, A., Saiz, P. A., Parellada, M., … FLAMM-PEPs study—Centro de Investigacio´n Biome´dica en Red de Salud Mental. (2013). Peripheral endocannabinoid system dysregulation in first-episode psychosis. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 38(13), 2568-2577. https://doi.org/10.1038/npp.2013.165

Bisogno, T., Mahadevan, A., Coccurello, R., Chang, J. W., Allarà, M., Chen, Y., … Di Marzo, V. (2013). A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-Obesity effects. British Journal of Pharmacology, 169(4), 784-793. https://doi.org/10.1111/bph.12013

Buczynski, M. W., Herman, M. A., Hsu, K.-L., Natividad, L. A., Irimia, C., Polis, I. Y., … Parsons, L. H. (2016). Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proceedings of the National Academy of Sciences of the United States of America, 113(4), 1086-1091. https://doi.org/10.1073/pnas.1522672113

Deng, H., Kooijman, S., van den Nieuwendijk, A. M. C. H., Ogasawara, D., van der Wel, T., van Dalen, F., … van der Stelt, M. (2017). Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding. Journal of Medicinal Chemistry, 60(1), 428-440. https://doi.org/10.1021/acs.jmedchem.6b01482

Engeli, S., Lehmann, A.-C., Kaminski, J., Haas, V., Janke, J., Zoerner, A. A., … Jordan, J. (2014). Influence of dietary fat intake on the endocannabinoid system in lean and obese subjects. Obesity, 22(5), E70-E76. https://doi.org/10.1002/oby.20728

Gao, Y., Vasilyev, D. V., Goncalves, M. B., Howell, F. V., Hobbs, C., Reisenberg, M., … Doherty, P. (2010). Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30(6), 2017-2024. https://doi.org/10.1523/JNEUROSCI.5693-09.2010

Gaveglio, V. L., Pascual, A. C., Giusto, N. M., & Pasquaré, S. J. (2016). Age-related changes in retinoic, docosahexaenoic and arachidonic acid modulation in nuclear lipid metabolism. Archives of Biochemistry and Biophysics, 604, 121-127. https://doi.org/10.1016/j.abb.2016.06.017

Gomez, O., Arevalo-Martin, A., Garcia-Ovejero, D., Ortega-Gutierrez, S., Cisneros, J. A., Almazan, G., … Molina-Holgado, E. (2010). The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia, 58(16), 1913-1927. https://doi.org/10.1002/glia.21061

Goncalves, M. B., Suetterlin, P., Yip, P., Molina-Holgado, F., Walker, D. J., Oudin, M. J., … Doherty, P. (2008). A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner. Molecular and Cellular Neuroscience, 38(4), 526-536. https://doi.org/10.1016/j.mcn.2008.05.001

Janssen, F. J., & van der Stelt, M. (2016). Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders. Bioorganic & Medicinal Chemistry Letters, 26(16), 3831-3837. https://doi.org/10.1016/j.bmcl.2016.06.076

Jenniches, I., Ternes, S., Albayram, O., Otte, D. M., Bach, K., Bindila, L., … Zimmer, A. (2016). Anxiety, Stress, and Fear Response in Mice With Reduced endocannabinoid Levels. Biological Psychiatry, 79(10), 858-868. https://doi.org/10.1016/j.biopsych.2015.03.033

Lin, Y.-H., Chen, Y.-C., Kao, T.-Y., Lin, Y.-C., Hsu, T.-E., Wu, Y.-C., … Wang, H.-D. (2014). Diacylglycerol lipase regulates lifespan and oxidative stress response by inversely modulating TOR signaling in Drosophila and C. elegans. Aging Cell, 13(4), 755-764. https://doi.org/10.1111/acel.12232

Marinelli, S., Pacioni, S., Bisogno, T., Di Marzo, V., Prince, D. A., Huguenard, J. R., & Bacci, A. (2008). The endocannabinoid 2-arachidonoylglycerol is responsible for the slow self-inhibition in neocortical interneurons. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(50), 13532-13541. https://doi.org/10.1523/JNEUROSCI.0847-08.2008

Martella, A., Sepe, R. M., Silvestri, C., Zang, J., Fasano, G., Carnevali, O., … Marzo, V. D. (2016). Important role of endocannabinoid signaling in the development of functional vision and locomotion in zebrafish. The FASEB Journal, 30(12), 4275-4288. https://doi.org/10.1096/fj.201600602R

Matthews, A. T., Lee, J. H., Borazjani, A., Mangum, L. C., Hou, X., & Ross, M. K. (2016). Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase. American Journal of Physiology - Cell Physiology, 311(6), C960-C974. https://doi.org/10.1152/ajpcell.00251.2015

Ogasawara, D., Deng, H., Viader, A., Baggelaar, M. P., Breman, A., den Dulk, H., … van der Stelt, M. (2016). Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proceedings of the National Academy of Sciences of the United States of America, 113(1), 26-33. https://doi.org/10.1073/pnas.1522364112

Oudin, M. J., Gajendra, S., Williams, G., Hobbs, C., Lalli, G., & Doherty, P. (2011). endocannabinoids regulate the migration of subventricular zone-derived neuroblasts in the postnatal brain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(11), 4000-4011. https://doi.org/10.1523/JNEUROSCI.5483-10.2011

Oudin, M. J., Hobbs, C., & Doherty, P. (2011). DAGL-dependent endocannabinoid signalling: roles in axonal pathfinding, synaptic plasticity and adult neurogenesis. European Journal of Neuroscience, 34(10), 1634-1646. https://doi.org/10.1111/j.1460-9568.2011.07831.x

Pascual, A. C., Gaveglio, V. L., Giusto, N. M., & Pasquaré, S. J. (2014). cannabinoid receptor-dependent metabolism of 2-arachidonoylglycerol during aging. Experimental Gerontology, 55, 134-142. https://doi.org/10.1016/j.exger.2014.04.008

Pascual, A. C., Gaveglio, V. L., Giusto, N. M., & Pasquaré, S. J. (s. f.). 2-arachidonoylglycerol metabolism is differently modulated by oligomeric and fibrillar conformations of amyloid beta in synaptic terminals. Neuroscience. https://doi.org/10.1016/j.neuroscience.2017.08.042

Pascual, A. C., Gaveglio, Giusto, N. M., & Pasquaré, S. J. (2013). Aging modifies the enzymatic activities involved in 2-arachidonoylglycerol metabolism. BioFactors, 39(2), 209-220. https://doi.org/10.1002/biof.1055

Pasquaré, S. J., Gaveglio, V. L., & Giusto, N. M. (2009). Age-related changes in the metabolization of phosphatidic acid in rat cerebral cortex synaptosomes. Archives of Biochemistry and Biophysics, 488(2), 121-129.

Pérez-Morales, M., Fajardo-Valdez, A., Méndez-Díaz, M., Ruiz-Contreras, A. E., & Prospéro-García, O. (2014). 2-Arachidonoylglycerol into the lateral hypothalamus improves reduced sleep in adult rats subjected to maternal separation. Neuroreport, 25(18), 1437-1441. https://doi.org/10.1097/WNR.0000000000000287

Subbanna, S., Psychoyos, D., Xie, S., & Basavarajappa, B. S. (2015). Postnatal ethanol exposure alters levels of 2-arachidonylglycerol-metabolizing enzymes and pharmacological inhibition of monoacylglycerol lipase does not cause neurodegeneration in neonatal mice. Journal of Neurochemistry, 134(2), 276-287. https://doi.org/10.1111/jnc.13120

Tung, L.-W., Lu, G.-L., Lee, Y.-H., Yu, L., Lee, H.-J., Leishman, E., … Chiou, L.-C. (2016). Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nature Communications, 7, 12199. https://doi.org/10.1038/ncomms12199

Wang, X.-Q., Ma, J., Cui, W., Yuan, W.-X., Zhu, G., Yang, Q., … Gao, G.-D. (2016). The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL-α expression following short-term morphine withdrawal. British Journal of Pharmacology, 173(7), 1143-1153. https://doi.org/10.1111/bph.12969

Wilkerson, J. L., Ghosh, S., Bagdas, D., Mason, B. L., Crowe, M. S., Hsu, K. L., … Lichtman, A. H. (2016). Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. British Journal of Pharmacology, 173(10), 1678-1692. https://doi.org/10.1111/bph.13469

Yoshino, H., Miyamae, T., Hansen, G., Zambrowicz, B., Flynn, M., Pedicord, D., … Gonzalez-Burgos, G. (2011). Postsynaptic diacylglycerol lipase mediates retrograde endocannabinoid suppression of inhibition in mouse prefrontal cortex. The Journal of Physiology, 589(Pt 20), 4857-4884. https://doi.org/10.1113/jphysiol.2011.212225

Zhou, Y., Oudin, M. J., Gajendra, S., Sonego, M., Falenta, K., Williams, G., … Doherty, P. (2015). Regional effects of endocannabinoid, BDNF and FGF receptor signalling on neuroblast motility and guidance along the rostral migratory stream. Molecular and Cellular Neurosciences, 64, 32-43. https://doi.org/10.1016/j.mcn.2014.12.001

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