Inflammation causes insulin resistance via IRF3-mediated reduction in FAHFA levels

ABSTRACT: 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

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, White Adipose Tissue, Kidney

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Radu Suciu  

LAB HEAD: Evan D. Rosen

PROVIDER: PXD047864 | Pride | 2024-03-14

REPOSITORIES: Pride