PULMONARY MYELOPEROXIDASE ACTIVITY WORSENS INSULIN RESISTANCE IN OBESE MICE

DELLA-VEDOVA MC; MUNOZ, MD; ER VERNI; SANTILLAN, LUCAS; GOMEZ N,; GOMEZ MEJIBA, SE; RAMIREZ DC

Congreso; SAIC; 2016

Neutrophilic inflammation (NI) is a poorly known processoccurring in the obese lung that may determine many obesityassociated metabolic abnormalities, including insulin resistance(IR). At sites of NI myeloperoxidase (MPO) oxidizes chlorideanions to hypochlorous acid or hypochlorite (HOCl/OCl-) whichcan damage the lung, increase systemic oxidative stress/inflammation and thus worsen IR. Bacterial lipopolisaccharide (LPS) isa stressor that when administrated by intratracheal instillation (ITI)causes NI in the lung. Hydrazide 4-aminobenzoic acid (ABAH) isa fairly-specific inhibitor of MPO. Taurine is a non-cell permeablescavenger of HOCl. Herein we hypothesized that inhibition of oxidative processes mediated by MPO in the obese lung can reduceIR in obesity. To test this hypothesis we used male B6 mice whichwere fed a high-fat diet and fructose (obese) and a low-fat diet andtap-water (control). During the last week of diet mice both group ofmice were ITI once a day with either PBS (vehicle), ABAH (10 uM/mouse) or taurine (5nM/mouse). The last day of diet animals wereITI with 2.5 ug LPS/mouse or PBS alone; and 6 h later a glucosetolerance test was performed. A total of 6 groups for control andobese mice were compared (PBS, LPS, ABAH, ABAH+LPS, Tauand Tau+LPS). Compared to control, LPS treatment to obese miceincreases more lung MPO activity, chlorotyrosine, nitrotyrosine,TNF-a and reduce insulin sensitivity. These differences betweencontrol and obese mice upon treatment with LPS were abrogatedwhen animals were pre-treated with either ABAH or taurine. Weconclude that MPO-driven oxidative modification in the lung ofobese animals are responsible for worsening IR and may providea therapeutic target to reduce IR in obese subjects. Supported byPROICO 2-3214 & PICT-2014-3369 (to DCR), PROICO 10-0414(To SEGM) and PIP2015-2017-112215-0100603CO (To DCR,