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

Daisuke Ogasawara; Hui Deng; Andreu Viader; Marc P Baggelaar; Arjen Breman; Hans den Dulk; Adrianus M C H van den Nieuwendijk; Marjolein Soethoudt; Tom van der Wel; Juan Zhou; Herman S Overkleeft; Manuel Sanchez-Alavez; Simone Mori; William Nguyen; Bruno Conti; Xiaojie Liu; Yao Chen; Qing-Song Liu; Benjamin F Cravatt; Mario van der Stelt

doi:10.1073/pnas.1522364112

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

Daisuke Ogasawara, Hui Deng, Andreu Viader, Marc P Baggelaar, Arjen Breman, Hans den Dulk, Adrianus M C H van den Nieuwendijk, Marjolein Soethoudt, Tom van der Wel, Juan Zhou, Herman S Overkleeft, Manuel Sanchez-Alavez, Simone Mori, William Nguyen, Bruno Conti, Xiaojie Liu, Yao Chen, Qing-Song Liu, Benjamin F Cravatt, Mario van der Stelt

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	26-33
Number of pages	8
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	1
DOIs	https://doi.org/10.1073/pnas.1522364112
Publication status	Published - 5 Jan 2016
Externally published	Yes

Keywords

Animals
Arachidonic Acids/metabolism
Brain/drug effects
Diglycerides/metabolism
Endocannabinoids/metabolism
Enzyme Inhibitors/chemistry
Glycerides/metabolism
Lipoprotein Lipase/antagonists & inhibitors
Male
Mice
Mice, Inbred C57BL
Neuronal Plasticity/drug effects
Receptors, Cannabinoid/metabolism
Signal Transduction/drug effects

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10.1073/pnas.1522364112

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Ogasawara, D., Deng, H., Viader, A., Baggelaar, M. P., Breman, A., den Dulk, H., van den Nieuwendijk, A. M. C. H., Soethoudt, M., van der Wel, T., Zhou, J., Overkleeft, H. S., Sanchez-Alavez, M., Mori, S., Nguyen, W., Conti, B., Liu, X., Chen, Y., Liu, Q.-S., Cravatt, B. F., & van der Stelt, M. (2016). Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proceedings of the National Academy of Sciences of the United States of America, 113(1), 26-33. https://doi.org/10.1073/pnas.1522364112

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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.",

keywords = "Animals, Arachidonic Acids/metabolism, Brain/drug effects, Diglycerides/metabolism, Endocannabinoids/metabolism, Enzyme Inhibitors/chemistry, Glycerides/metabolism, Lipoprotein Lipase/antagonists & inhibitors, Male, Mice, Mice, Inbred C57BL, Neuronal Plasticity/drug effects, Receptors, Cannabinoid/metabolism, Signal Transduction/drug effects",

author = "Daisuke Ogasawara and Hui Deng and Andreu Viader and Baggelaar, {Marc P} and Arjen Breman and {den Dulk}, Hans and {van den Nieuwendijk}, {Adrianus M C H} and Marjolein Soethoudt and {van der Wel}, Tom and Juan Zhou and Overkleeft, {Herman S} and Manuel Sanchez-Alavez and Simone Mori and William Nguyen and Bruno Conti and Xiaojie Liu and Yao Chen and Qing-Song Liu and Cravatt, {Benjamin F} and {van der Stelt}, Mario",

year = "2016",

month = jan,

day = "5",

doi = "10.1073/pnas.1522364112",

language = "English",

volume = "113",

pages = "26--33",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Ogasawara, D, Deng, H, Viader, A, Baggelaar, MP, Breman, A, den Dulk, H, van den Nieuwendijk, AMCH, Soethoudt, M, van der Wel, T, Zhou, J, Overkleeft, HS, Sanchez-Alavez, M, Mori, S, Nguyen, W, Conti, B, Liu, X, Chen, Y, Liu, Q-S, Cravatt, BF & van der Stelt, M 2016, 'Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 1, pp. 26-33. https://doi.org/10.1073/pnas.1522364112

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T1 - Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

AU - Ogasawara, Daisuke

AU - Deng, Hui

AU - Viader, Andreu

AU - Baggelaar, Marc P

AU - Breman, Arjen

AU - den Dulk, Hans

AU - van den Nieuwendijk, Adrianus M C H

AU - Soethoudt, Marjolein

AU - van der Wel, Tom

AU - Zhou, Juan

AU - Overkleeft, Herman S

AU - Sanchez-Alavez, Manuel

AU - Mori, Simone

AU - Nguyen, William

AU - Conti, Bruno

AU - Liu, Xiaojie

AU - Chen, Yao

AU - Liu, Qing-Song

AU - Cravatt, Benjamin F

AU - van der Stelt, Mario

PY - 2016/1/5

Y1 - 2016/1/5

N2 - 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.

AB - 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.

KW - Animals

KW - Arachidonic Acids/metabolism

KW - Brain/drug effects

KW - Diglycerides/metabolism

KW - Endocannabinoids/metabolism

KW - Enzyme Inhibitors/chemistry

KW - Glycerides/metabolism

KW - Lipoprotein Lipase/antagonists & inhibitors

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Neuronal Plasticity/drug effects

KW - Receptors, Cannabinoid/metabolism

KW - Signal Transduction/drug effects

U2 - 10.1073/pnas.1522364112

DO - 10.1073/pnas.1522364112

M3 - Article

C2 - 26668358

SN - 0027-8424

VL - 113

SP - 26

EP - 33

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 1

ER -

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

Abstract

Keywords

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