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Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

Academic Article
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Overview

related to degree

  • Ogasawara, Daisuke, Ph.D. in Chemical Biology, Scripps Research 2013 - 2019

authors

  • Ogasawara, Daisuke
  • Deng, H.
  • Viader, A.
  • Baggelaar, M. P.
  • Breman, A.
  • den Dulk, H.
  • van den Nieuwendijk, A. M. C. H. and Soethoudt, M.
  • van der Wel, T.
  • Zhou, J.
  • Overkleeft, H. S.
  • Sanchez-Alavez, Manuel
  • Mo, S.
  • Nguyen, W.
  • Conti, Bruno
  • Liu, X.
  • Chen, Y.
  • Liu, Q. S.
  • Cravatt, Benjamin
  • van der Stelt, M.

publication date

  • 2016

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.

subject areas

  • Animals
  • Arachidonic Acids
  • Brain
  • Diglycerides
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • Lipoprotein Lipase
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity
  • Receptors, Cannabinoid
  • Signal Transduction
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Identity

PubMed Central ID

  • PMC4711871

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1522364112

PubMed ID

  • 26668358
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Additional Document Info

start page

  • 26

volume

  • 113

issue

  • 1

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