Obesity, Rather Than Fat Content Of Diet, Contributes To Reduced Influenza Vaccine Efficacy In Mice Fed A High Fat Diet

Recent studies have suggested that obesity may be associated with impaired immune function as well as the related reduction in resistance to infection. The most commonly utilized animal model for diet‐induced obesity involves feeding mice a high fat (HF) diet (typically providing 45% or 60% Calories as fat). Since HF diets are also known to affect immune cell function, it is difficult to determine whether, and to what extent, the reported findings are a result of the influence of obesity on immune function and resistance to infection or a direct result of the high fat content of the diet used. To address this, female CD‐1 mice (1‐mo) were weight‐matched and fed either a HF (45%) diet or low fat (LF, 10%) control diet. After 5‐mo on the respective diets, LF mice weighed 36.7 ± 2.9 g. Since the CD‐1 mice had considerable variation in the degree of weight gain in response to high fat diet, we further divided the HF fed mice, based on body weight, into two sub‐groups: HF lean (HFL, <40 g, average 36.5 ± 1.3 g) and HF obese (HFO, >40 g, average 50.8 ± 4.0 g). Mice were immunized with an influenza A/Puerto Rico/8/34 vaccine and boosted 3‐wk later. Blood was collected 4‐wk after the booster for antibody titer analysis. Mice were infected one week later with influenza A/Puerto Rico/8/34 virus and monitored daily for clinical signs including weight loss. One‐month after infection, mice were euthanized and tissues collected for analysis. Vaccinated mice had significantly less weight loss than unvaccinated control mice after infection, which validated the effectiveness of both infection and vaccine protection. Among vaccinated mice, LF and HFL mice largely maintained their weight while HFO mice demonstrated significant weight loss (average 10%). Further, there was a significant, positive correlation between initial weight and post‐infection weight loss (r=0.66, p<0.001). There was no difference in Ab titer, suggesting that the obesity‐induced decrease in vaccine efficacy might be mediated through changes in other immune responses that were involved in the influenza infection. HFO mice had lower lymphocyte proliferation stimulated by anti‐CD3/CD28 (p=0.05) or T cell mitogen concanavalin A (Con A) (p<0.05), and showed a strong trend toward higher interferon‐γ production (p=0.062 and 0.056 for anti‐CD3/CD28 and Con A stimulation, respectively) when compared to HFL mice. There was no significant difference between the groups in the inflammatory cytokines interleukin (IL)‐1β, IL‐6, and tumor necrosis factor (TNF)‐α levels in lung homogenates, or LPS‐induced ex vivo production of these cytokines in splenocytes; no difference was found in immune cell phenotype (T cells, CD4 T cells, CD8 T cells, B cells, natural killer cells, macrophages), and CD3/CD28‐ or Con A‐stimulated production of IL‐2, IL‐4, and TNF‐α in splenocytes. Taken together our results suggest that obesity, rather than the high fat intake employed to achieve the obese state, is responsible for the diminished vaccine efficacy and altered immune responses. Support or Funding Information Supported by the USDA under contract #58‐1950‐4‐003.