title: Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition.
abstract: 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.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogasawara
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Hui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Andreu
authors.initials: A
authors.lastname: Viader
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Marc P
authors.initials: MP
authors.lastname: Baggelaar
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Arjen
authors.initials: A
authors.lastname: Breman
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Hans
authors.initials: H
authors.lastname: den Dulk
authors.forename: Adrianus M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Adriann M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Marjolein
authors.initials: M
authors.lastname: Soethoudt
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Tom
authors.initials: T
authors.lastname: van der Wel
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez-Alavez
authors.forename: Simone
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Simone
authors.initials: S
authors.lastname: Mo
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: William
authors.initials: W
authors.lastname: Nguyen
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Bruno
authors.initials: B
authors.lastname: Conti
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Qing-Song
authors.initials: QS
authors.lastname: Liu
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; cravatt@scripps.edu m.van.der.stelt@chem.leidenuniv.nl.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands; cravatt@scripps.edu m.van.der.stelt@chem.leidenuniv.nl.
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005989:Glycerides / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C011439:1,2-diacylglycerol; D001095:Arachidonic Acids; D004075:Diglycerides; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D043882:Receptors, Cannabinoid; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase; C577904:diacylglycerol lipase beta, mouse
keywords: endocannabinoid; inhibitor; lipase; nervous system