| Title : Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition - Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26 |
| Author(s) : Ogasawara D , Deng H , Viader A , Baggelaar MP , Breman A , den Dulk H , van den Nieuwendijk AM , Soethoudt M , van der Wel T , Zhou J , Overkleeft HS , Sanchez-Alavez M , Mori S , Nguyen W , Conti B , Liu X , Chen Y , Liu QS , Cravatt BF , van der Stelt M |
| Ref : Proc Natl Acad Sci U S A , 113 :26 , 2016 |
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Abstract :
Diacylglycerol lipases (DAGLalpha and DAGLbeta) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLalpha is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network. |
| PubMedSearch : Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26 |
| PubMedID: 26668358 |
| Gene_locus related to this paper: human-DAGLA , human-DAGLB |
| Inhibitor | DH376 DO34 |
| Gene_locus | human-DAGLA human-DAGLB |
| Family | Lipase_3 |
Ogasawara D, Deng H, Viader A, Baggelaar MP, Breman A, den Dulk H, van den Nieuwendijk AM, Soethoudt M, van der Wel T, Zhou J, Overkleeft HS, Sanchez-Alavez M, Mori S, Nguyen W, Conti B, Liu X, Chen Y, Liu QS, Cravatt BF, van der Stelt M (2016)
Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition
Proc Natl Acad Sci U S A
113 :26
Ogasawara D, Deng H, Viader A, Baggelaar MP, Breman A, den Dulk H, van den Nieuwendijk AM, Soethoudt M, van der Wel T, Zhou J, Overkleeft HS, Sanchez-Alavez M, Mori S, Nguyen W, Conti B, Liu X, Chen Y, Liu QS, Cravatt BF, van der Stelt M (2016)
Proc Natl Acad Sci U S A
113 :26