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Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism

ABSTRACT: This submission includes MS data for the paper titled "Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism", submitted to Cell Chemical Biology.Summary:Diacylglycerol lipase (DAGL) produce 2-arachidonoylglycerol (2-AG) and other proinflammatory lipids. Inactivation of DAGLs reduces the production of 2-AG, arachidonic acid (AA) and eicosanoids and elicits antinociceptive and anti-(neuro)inflammatory effects in rodents. However, inhibitors that enter the brain can cause significant central nervous system (CNS) side effects. Using activity-based protein profiling (ABPP), we report the discovery of A1480LS, a potent, in vivo active, small molecule dual inhibitor of DAGLα/β that is functionally biased to the periphery. We demonstrate that A1480LS reduces pain in animal models of both inflammatory and neuropathic pain. Moreover, A1480LS accomplishes this by reducing 2-AG and other lipids in peripheral tissues, all without causing adverse CNS effects of seizures. Overall, we show that inhibiting DAG metabolism in the periphery elicits antinociceptive effects that can be functionally dissected from adverse central effects and provide preclinical validation for a non-narcotic strategy to treat pain.Raw files for the selectivity experiment profiling of A1480LS in THP1 cells are listed below. Search and quantification results bearing the same file stem are also provided, as well as the fasta database that was used: uniprot_HumanComplete_121105_cdhit98_plus_Reverse_wContaminants150305.fasta.- RAH-NB1-208_A_03.rawRaw files for the in vivo time course experiment in rat kidneys are listed below. A Skyline export bearing the same name is also provided, as well as the fasta database that was used: uniprot_6organism_constructs_contaminants_20190213_forPRMJOB.fasta.- NN-NB2-213_A1.raw: 0h, Vehicle- NN-NB2-213_A2.raw: 0h, Vehicle- NN-NB2-213_A3.raw: 0h, Vehicle- NN-NB2-213_A4.raw: 0h, Vehicle- NN-NB2-213_B1.raw: 1h, A1480LS- NN-NB2-213_B2.raw: 1h, A1480LS- NN-NB2-213_B3.raw: 1h, A1480LS- NN-NB2-213_B4.raw: 1h, A1480LS- NN-NB2-213_B5.raw: 4h, A1480LS- NN-NB2-213_B6.raw: 4h, A1480LS- NN-NB2-213_B7.raw: 4h, A1480LS- NN-NB2-213_B8.raw: 4h, A1480LS- NN-NB2-213_B9.raw: 8h, A1480LS- NN-NB2-213_B10.raw: 8h, A1480LS- NN-NB2-213_B11.raw: 8h, A1480LS- NN-NB2-213_B12.raw: 12h, A1480LS- NN-NB2-213_C1.raw: 12h, A1480LS- NN-NB2-213_C2.raw: 12h, A1480LS- NN-NB2-213_C3.raw: 12h, A1480LS- NN-NB2-213_C4.raw: 24h, A1480LS- NN-NB2-213_C5.raw: 24h, A1480LS- NN-NB2-213_C6.raw: 24h, A1480LS- NN-NB2-213_C7.raw: 24h, A1480LS- NN-NB2-213_C8.raw: 32h, A1480LS- NN-NB2-213_C9.raw: 32h, A1480LS- NN-NB2-213_C10.raw: 32h, A1480LS- NN-NB2-213_C11.raw: 32h, A1480LS

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat) Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Monocyte, Kidney

SUBMITTER: Radu Suciu

LAB HEAD: Jason R.

PROVIDER: PXD069894 | Pride | 2026-01-16

REPOSITORIES: Pride

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Project description:Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity. ## File Key ### MS-ABPP The following raw files were acquired on an Eclipse instrument in triplicate with two concentrations of inhibitor in both brain and kidney. These variables are encoded in the file names. Associated analysis pipeline files from CIMAGE are provided for each raw file (same file name, with a .raw_output_rt_10_sn_2.5.to_excel extension). - brain_conc1.0_rep1.raw - brain_conc1.0_rep2.raw - brain_conc1.0_rep3.raw - brain_conc10.0_rep1.raw - brain_conc10.0_rep2.raw - brain_conc10.0_rep3.raw - kidney_conc1.0_rep1.raw - kidney_conc1.0_rep2.raw - kidney_conc1.0_rep3.raw - kidney_conc10.0_rep1.raw - kidney_conc10.0_rep2.raw - kidney_conc10.0_rep3.raw ### TMT Dose Response The following raw files were acquired on an Eclipse instrument instrument in both brain and white adipose tissues: - brain_dose_response.raw - wat_dose_response.raw The TMT channels were organized as follows: - DMSO channels: 1, 3, 5 - ABD-110 @ 0.001 μM: 7, 9, 11 - ABD-110 @ 0.01 μM: 2, 4, 6 - ABD-110 @ 0.1 μM: 13, 15, 17 - ABD-110 @ 1 μM: 8, 10, 12 - ABD-110 @ 10 μM: 14, 16, 18 Associated analysis pipeline files after IDFilter run are provided for each file (same file name, with a _filtered_matches suffix and an .idXML extension). ### PRM AIG1 In Vivo Target Engagement The A prefix before the replicate number refers to treatment with ABD-110, whereas the V prefix refers to vehicle treatment. Diet and tissue type are also encoded in the filename. The following files were acquired on a Lumos instrument, with 5 replicates for each condition (as noted in square brackets). Associated pipeline analysis files are Skyline exports and are provided as two .csv files having names beginning with Skyline_PRM_export and ending with the tissue types contained. - Brain_Chow_A[1-5].raw - Brain_Chow_V[1-5].raw - Brain_HVD_A[1-5].raw - Brain_HVD_V[1-5].raw - eWAT_Chow_A[1-5].raw - eWAT_Chow_V[1-5].raw - eWAT_HVD_A[1-5].raw - eWAT_HVD_V[1-5].raw - iWAT_Chow_A[1-5].raw - iWAT_Chow_V[1-5].raw - iWAT_HVD_A[1-5].raw - iWAT_HVD_V[1-5].raw - Kindey_Chow_A[1-5].raw - Kindey_Chow_V[1-5].raw - Kindey_HVD_A[1-5].raw - Kindey_HVD_V[1-5].raw

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Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism

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			Action	DRS
	NN-NB2-213_A1.raw	Raw
	NN-NB2-213_A2.raw	Raw
	NN-NB2-213_A3.raw	Raw
	NN-NB2-213_A4.raw	Raw
	NN-NB2-213_B1.raw	Raw