Chronic Trypanosoma cruzi infection potentiates adipose tissue macrophage polarization toward an anti-inflammatory M2 phenotype and contributes to diabetes progression in a diet-induced obesity model

// María E. Cabalén 1 , María F. Cabral 1 , Liliana M. Sanmarco 2 , Marta C. Andrada 1 , Luisina I. Onofrio 2 , Nicolás E. Ponce 2 , María P. Aoki 2 , Susana Gea 2 and Roxana C. Cano 1,2 1 Facultad de Ciencias Químicas, UA Área CS. AGR. ING. BIO Y S CONICET. Universidad Católica de Córdoba, Córdoba, Argentina 2 Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Córdoba, Argentina Correspondence to: María E. Cabalén, email: // Roxana C. Cano, email: // Keywords : obesity, immunometabolism, adipose tissue macrophages, innate immunity, Trypanosoma cruzi, Immunology and Microbiology Section, Immune response, Immunity Received : June 24, 2015 Accepted : January 12, 2016 Published : February 23, 2016 Abstract Chronic obesity and Chagas disease (caused by the protozoan Trypanosoma cruzi ) represent serious public health concerns. The interrelation between parasite infection, adipose tissue, immune system and metabolism in an obesogenic context, has not been entirely explored. A novel diet-induced obesity model (DIO) was developed in C57BL/6 wild type mice to examine the effect of chronic infection (DIO+I) on metabolic parameters and on obesity-related disorders. Dyslipidemia, hyperleptinemia, and cardiac/hepatic steatosis were strongly developed in DIO mice. Strikingly, although these metabolic alterations were collectively improved by infection, plasmatic apoB100 levels remain significantly increased in DIO+I, suggesting the presence of pro-atherogenic small and dense LDL particles. Moreover, acute insulin resistance followed by chronic hyperglycemia with hypoinsulinemia was found, evidencing an infection-related-diabetes progression. These lipid and glucose metabolic changes seemed to be highly dependent on TLR4 expression since TLR4-/- mice were protected from obesity and its complications. Notably, chronic infection promoted a strong increase in MCP-1 producing macrophages with a M2 (F4/80+CD11c-CD206+) phenotype associated to oxidative stress in visceral adipose tissue of DIO+I mice. Importantly, infection reduced lipid content but intensified inflammatory infiltrates in target tissues. Thus, parasite persistence in an obesogenic environment and the resulting host immunometabolic dysregulation may contribute to diabetes/atherosclerosis progression.