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

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.

Alterations in pancreatic β cell function and Trypanosoma cruzi infection: evidence from human and animal studies

“…To date, a relationship between T. cruzi infection and insulin resistance particularly as it applies to adipocyte function has been noted (Cabalen et al 2016; Nagajyothi et al 2009) but outcomes on the performance of insulin secreting β cells, not extensively studied. This concept however, has been widely examined in bacterial sepsis.…”

Adipose Tissue: A Safe Haven for Parasites?

“…With respect to macrophage populations, there is a balance between pro-inflammatory M1 macrophages, and macrophages expressing a gene expression profile more consistent with a role in remodeling (M2 macrophages) [45]. During a T. cruzi mouse infection, a shift towards M2 macrophages has been described, which could help maintaining tissue homeostasis or promoting parasite survival [46]. However, it remains unknown if the M1 response is muted.…”

Dysregulated Network of Immune, Endocrine and Metabolic Markers is Associated to More Severe Human Chronic Chagas Cardiomyopathy

“…Until a few years ago, the impact that this set of variables could have had on the severity of CCC was poorly appreciated. Nevertheless, some evidence from laboratory animals and human studies suggests that metabolic alterations triggered by the western lifestyle can influence the progression of Chagas disease [14,19].…”

“…Coincidentally, another study detected a higher prevalence of diabetes in chagasic women with chronic myocarditis than in the general population [13]. Moreover, a recent work in chronically T. cruzi-infected mice showed that an obesogenic context promotes the development of cardiovascular disorders [14].…”