Scavenging of intracellularly produced HOCl with resveratrol protects insulin signaling in adipocytes

FLORENCIA NAHIR CLAVELES CASAS,; CHACON I. DEL V; DARIO C RAMIREZ; LOPEZ CM; KATHLEEN HINOJOSA VERA; GOMEZ MEJIBA, SANDRA;; BARRERAS, FS; DI SCIULLO MP,; AIRTON ROMAN AGUILAR

LAS Vegas Nevada

Congreso; S. of Free Radical Biology and Medicine; 2019

SFRBM

Resveratrol is a cell permeable trans-stilbene derivative that can scavenge intracellularly produced HOCl (J. Biol. Chem, 285:20062/71). Our diet-induced obesity B6-mouse model showed that epididimal AT expresses myeloperoxidase (MPO) in adipose tissue macrophages (ATM) that also express M1-pro-inflammatory markers (e.g., IL-6, iNOS). MPO expression was observed in ATM located in the typical crown-like structures; and also inside adipocytes. Tissue fractionation showed MPO mRNA in the ATM, but not in the stromal-vascular fraction. Treatment of these isolated adipocytes with H2O2 blocked glucose uptake. Based on these findings, we hypothesized that MPO interferes with AT insulin signaling by producing HOCl and causing oxidation of intracellular components involved in insulin-triggered signaling. To test this hypothesis we differentiated human adipocytes and loaded them with human MPO. Treatment of MPO-loaded adipocytes with H2O2 caused intracellular production of HOCl, reduced insulin-triggered GLUT-4 translocation to the membrane and glucose uptake. Furthermore DMPO-based immuno-spin trapping and MS-tandem showed radicalization of specific components of the insulin signaling (e.g., IRS-1/2, SOCS3, GLUT-4). These effects were prevented by resveratrol, but not by taurine or methionine because these cannot pass across the membrane. Together our findings suggest that resveratrol can protect insulin sensitivity in the obese AT by scavenging intracellularly produced HOCl.These findings are also in agreement with the role of resveratrol in protecting genomic DNA against intracellularly produced HOCl in MPO-loaded epithelial cells.