Myeloperoxidase and Protein-radicalization are Linked to Insulin Resistance in the Obese Adipose Tissue

CASAS, FLORENCIA CLAVELES; GOMEZ-MEJIBA, SANDRA; LOPEZ, CRISTOFER MARTÍN; RAMIREZ, DARIO; BARRERA, FLORENCIA; DI SCIULLO, MARIA

FREE RADICAL BIOLOGY AND MEDICINE

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2020 vol. 159

0891-5849

introduction: Our B6 mouse model of diet-induced obesity showed adipose tissue macrophages (ATM) forming typical crown-like structures in the adipose tissue (AT). These ATM from obese mice express 15-times more myeloperoxidase (MPO) mRNA than those from control mice. MPO protein, but not mRNA, was also found inside adipocytes in the obese AT. Treatment with the nitrone spin trap 5,5-dimethyl1-pyrroline N-oxide (DMPO) improved insulin sensitivity in obese mice. Objective: Based on these findings, we hypothesized that HOCl produced by MPO inside adipocytes interferes with insulin signaling in the AT. Methods: This may be caused by HOCl-induced radicalization and oxidation of specific proteins involved in insulin-triggered signaling. To test this hypothesis, we differentiated human adipocytes and loaded them with human MPO. Results: Treatment of MPOloaded adipocytes with H2O2 caused intracellular production of HOCl, radicalization of proteins, reduction of insulintriggered GLUT-4 translocation to the membrane, and reduced glucose uptake. Indeed, DMPO-based immuno-spin trapping and MS-tandem showed the radicalization of specific components of the insulin-triggered signaling (i.e., IRS-1/2, SOCS3 and GLUT-4). These effects were prevented by resveratrol that scavenged intracellularly produced HOCl thus preventing loss of insulin sensitivity. DMPO also prevented HOCl-induced loss of insulin sensitivity in adipocytes by trapping radicalized protein. Conclusion: Scavenging HOCl produced inside adipocytes with resveratrol or preventing protein oxidation with spin traps can protect insulin signaling in adipocytes