Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proc Natl Acad Sci U S A 2016 Jan 05;113(1):26-33
Date
12/17/2015Pubmed ID
26668358Pubmed Central ID
PMC4711871DOI
10.1073/pnas.1522364112Scopus ID
2-s2.0-84953225327 (requires institutional sign-in at Scopus site) 105 CitationsAbstract
Diacylglycerol lipases (DAGLα and DAGLβ) 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 DAGLα 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.
Author List
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 MAuthor
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsArachidonic Acids
Brain
Diglycerides
Endocannabinoids
Enzyme Inhibitors
Glycerides
Lipoprotein Lipase
Male
Mice
Mice, Inbred C57BL
Neuronal Plasticity
Receptors, Cannabinoid
Signal Transduction
