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).
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