Obesity-Associated Inflammatory Reprogramming Impairs a Granulomatous Response to Leishmania infantum

The demographics of leishmaniasis in Brazil have shifted in recent decades, coinciding with dietary changes and an increase in overweight/obesity. Cutaneous leishmaniasis becomes more treatment refractory in obese individuals, highlighting the impact of obesity on disease outcome. The impact of the overweight/obese state on infection with Leishmania infantum, which causes visceral leishmaniasis (VL), is unclear. We previously showed that an obesity-prone diet restricts L. infantum expansion in the livers of mice, but the immunological basis remained unexplored. Herein, we investigated whether this reflected improved granuloma formation and parasite control or a response to diet-induced hepatic steatosis and inflammation. To evaluate hepatic responses to VL during obesity, mice were maintained on a high-fat, high-cholesterol (HFHC) diet or a control diet before and throughout L. infantum infection. High-fat, high-cholesterol feeding significantly reduced hepatic parasite burdens but increased splenic parasite burdens. Control animals developed well-organized hepatic granulomas before local resolution, whereas HFHC-fed mouse livers developed diffuse inflammation and early fibrosis consistent with steatohepatitis. They completely failed to form mature granulomas. Quantitative analysis confirmed organized granulomas in 100% of infected control mice, whereas HFHC-fed infected mice showed no or else loosely aggregated, immature infiltrates in their livers. Transcriptional profiling revealed a pronounced inflammatory response in naïve HFHC-fed livers that was minimally exacerbated by infection. These data suggest that diet-induced obesity does not prevent an inflammatory response to the parasite. Rather, the obesity diet impairs formation of the tissue-specific granulomatous response that might normally contain L. infantum locally in the liver.