Weight loss-induced adipose macrophage memory improves local clearance in male mice.

Different stimuli can induce innate immune memory to improve pathogen defense or worsen cardiometabolic disease. However, it is less clear if the same stimuli can induce both the protective and detrimental effects of innate immune memory. We previously showed that weight loss induces innate immune memory in adipose macrophages that correlates with worsened diabetes risk after weight regain. In this study, we investigated the effect of weight loss on macrophage cytokine production and overall survival in a mouse model of infection. Male C57Bl/6J mice were put on high-fat or low-fat diets over 18 weeks to induce weight gain or weight loss. Lean mice served as controls. All mice were then infected IV with 2.5×10^6 CFU . Tissues were collected from 10 mice/group at day 3 and the remaining animals were followed for survival. Weight gain mice had the highest blood neutrophils and the highest bacterial burden in the kidney. However, there was no significant difference in survival. The weight loss group had the highest plasma TNF-α and a significant reduction in bacterial burden in the adipose tissue that correlated with increased adipose macrophage cytokine production. Thus, weight loss-induced adipose macrophage memory may both improve local clearance and worsen diabetes risk upon weight regain. Collectively, these findings support the notion that innate immune memory is an evolutionarily protective mechanism that also contributes to the development of cardiometabolic diseases.