THE NITRONE SPIN TRAP 5,5-DIMETHYL-1-PYRROLINE- N-OXIDE REDUCES HEPATIC NEUTROPHILIC INFLAMMATION AND INSULIN RESISTANCE IN A MOUSE MODEL OF DIET-INDUCED OBESITY

CARLA F. GUZMAN, Z1,2, 3, S3,3, DARIO C. RAMIREZ1, SANDRA E. GOMEZ MEJIBA2; INALEN DEL V. CHACON |; FLORENCIA SOLEDAD BARRERA,; JONATHAN M. RAMIREZ; LUCILA RIVEROS; IVANA MORALE; SONIA BARBIERIS; RAMÍREZ, DC.; GOMEZ MEJIBA, SANDRA;

Congreso; SAIC; 2024

A chronic positive-energy balance causes low-grade systemic inflammationin diet-induced obesity (DIO) models. This causes theactivation of the expression of inflammatory biomarkers, such asinducible nitric oxide synthase (iNOS), inflammatory cytokines, andadhesion molecules for neutrophils in tissue microvasculatures.In this study, our objective was to determine whether the nitrone5,5-dimethyl-1-pyrroline N-oxide (DMPO) is capable of reducinghepatic neutrophilic inflammation, and systemic inflammation; andconsequently improving insulin sensitivity in a DIO mouse model.To achieve this goal, we fed male C57 mice a control diet (CoD,rodent chow and tap water) or a hypercaloric diet (ObD, 22% bovinefat + 10% fructose in drinking water) for 24 weeks. Food and waterintake, body weight, and caloric intake were measured weekly. Atthe end of the dietary regime, serum IL-6, iNOS, nitrotyrosine formation(a marker of NO-induced oxidative stress), chlorotyrosine (amarker commonly used as a measure of neutrophilic inflammation),and MPO content were assessed by ELISA in liver homogenates.Mice fed the ObD for 24 weeks showed lower food intake than theCoD group, but higher water with fructose consumption, resultingin a higher total caloric intake, which was reflected in increasedbody weight, and higher epididymal fat content, adiposity index, andinsulin resistance (glucose tolerance test). Additionally, ObD miceshowed higher IL-6 concentration in serum, suggesting a state ofchronic systemic low-grade inflammation and insulin resistance.Mice injected with DMPO (2.5 mmol/mice/day for 7 days) or saline,a week before the end of the regimen, showed decreased hepaticinflammation, as well as improved insulin sensitivity, as compared tothose mice injected with saline. By blocking the expression of neutrophiladhesion molecules and pro-inflammatory cytokines, DMPOcan reduce hepatic neutrophilic inflammation and improve insulinresistance in obesity.