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

  • Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):26-33. doi: 10.1073/pnas.1522364112.
Daisuke Ogasawara  1 ,  Hui Deng  2 ,  Andreu Viader  1 ,  Marc P Baggelaar  2 ,  Arjen Breman  2 ,  Hans den Dulk  2 ,  Adrianus M C H van den Nieuwendijk ,  Marjolein Soethoudt  2 ,  Tom van der Wel  2 ,  Juan Zhou  2 ,  Herman S Overkleeft  3 ,  Manuel Sanchez-Alavez  1 ,  Simone Mori ,  William Nguyen  1 ,  Bruno Conti  1 ,  Xiaojie Liu  4 ,  Yao Chen  4 ,  Qing-Song Liu  4 ,  Benjamin F Cravatt  5 ,  Mario van der Stelt  6
Affiliations
  • 1. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
  • 2. Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
  • 3. Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands;
  • 4. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226.
  • 5. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; [email protected] [email protected].
  • 6. Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands; [email protected] [email protected].
PMID: 26668358 DOI: 10.1073/pnas.1522364112
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.

Keywords
endocannabinoid; inhibitor; lipase; nervous system.
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