Weight loss-induced adipose macrophage memory corresponds with lower adipose bacterial burden in murine systemic Staphylococcus aureus infection.

Abstract

Abstract: 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. Weight loss following high fat diet feeding induces innate immune memory in adipose macrophages that correlates with worsened diabetes risk after weight regain. Here, we investigated the effect of weight gain and loss on adipose macrophage memory and infection outcomes in systemic Staphylococcus aureus infection in C57Bl/6 J male mice. Lean controls remained on low-fat diet, weight gain mice started on low-fat diet and were moved to high-fat for 9 weeks, and weight loss mice began on high-fat diet for 9 weeks before moving to low-fat diet for 9 weeks. At 18 weeks, functional analyses were performed on adipose macrophages from each group of mice. Weight loss increased cytokine production and reactive oxygen species compared to lean controls. The remaining mice were infected intravenously with 2.5x10^8 colony forming units S.aureus. There was no effect of weight change on survival, however, weight gain reduced body temperature and increased sepsis scoring, blood neutrophils, and bacterial burden in the kidney. Weight loss increased plasma tumor necrosis factor (TNF-α) and adipose macrophage cytokine production that correlated with reduced bacterial burden in the adipose tissue. Thus, weight loss restores systemic infection defenses that are impaired with weight gain, and weight loss-induced adipose macrophage memory may further reduce local S. aureus growth. Collectively, innate immune memory to weight loss may be protective in local anti-microbial defense.