411 - Pulmonary Myeloperoxidase Activity Worsens Insulin Resistance in Obese Mice Exposed to Bacterial Endotoxin

Abstract

Neutrophilic inflammation (NI) is a poorly known process occurring in the lung of obese subjects exposed to indoor airborne pollutants that may worsen many obesity-associated metabolic abnormalities, including insulin resistance (IR). Indeed, obese patients exposed to indoor-airborne pollutants show worse IR than those unexposed, however the reasons for this disparity are partially known. Bacterial lipopolysaccharide (LPS) is a stressor that when administrated by intratracheal instillation (ITI) causes NI in the lung. At sites of NI, myeloperoxidase (MPO) oxidizes chloride anions to hypochlorous acid/hypochlorite (HOCl/OCl − ) which can damage the lung, increase systemic oxidative stress/inflammation and thus worsen IR. Hydrazide 4-aminobenzoic acid (ABAH) is a fairly-specific inhibitor of MPO. Taurine is a non-cell-permeable scavenger of HOCl. Herein we hypothesized that inhibition of oxidative processes mediated by MPO in the obese lung can reduce IR in obesity. To test this hypothesis we used male B6 mice which were fed a high-chicken-fat diet and fructose (obese) and a low-fat diet and tap-water (control). During the last week of diet and on a daily basis both groups of mice were ITI with either PBS (vehicle), ABAH (10 µmol/mouse) or taurine (5nmol/mouse). The last day-of-treatment animals were ITI with 2.5 µg LPS/mouse or PBS alone; and 6 h later an intraperitoneal glucose tolerance test was performed. A total of 6 groups, for both control and obese mice, were compared (PBS, LPS, ABAH, ABAH+LPS, Tau and Tau+LPS). Compared to control, LPS treatment to obese mice increased more lung MPO activity, chlorotyrosine, nitrotyrosine, TNF-α; but reduced insulin sensitivity. These differences between control and obese mice upon treatment with LPS were abrogated when animals were pre-treated with either ABAH or taurine. We conclude that MPO-driven oxidative modifications in the lung of obese animals are responsible for worsening IR when and may provide a therapeutic target to reduce IR in obese subjects exposed to indoor-airborne pollutants. Supported by PROICO 2-3214 & PICT-2014-3369 (to DCR), PROICO 10-0414 (To SEGM) and PIP2015-2017-112215-0100603CO (To DCR, SEA & SEGM).