Sex Differences Distinctly Impact High-Fat Diet-Induced Immune Dysfunction in Wistar Rats

ABSTRACT Background : Immune function is altered during obesity. Moreover, males and females across different species demonstrate distinct susceptibility to several diseases. However, less is known regarding the interplay between high-fat diet (HFD) and sex in the context of immune function. Objective The objective was to determine sex differences on immune function in response to a HFD compared to a control low-fat diet (LFD) in Wistar rats. Methods At 5 weeks of age, male and female Wistar rats were randomized to one of two diets for 9 weeks: ad libitum control LFD (20% kcal% fat, 53 kcal% carbohydrate, and 27 kcal% protein) or HFD (50% kcal% fat, 23 kcal% carbohydrate, and 27 kcal% protein). At 13 weeks of age, rats were euthanized and splenocytes were isolated. Immune cell subsets were determined by flow cytometry. Immune cell function was determined by measuring the ex vivo cytokine production following stimulation with mitogens. Two-way ANOVA was used to assess the main effect of sex, diet, and their interaction. Results : Males gained more weight compared to females (410 ± 46 vs 219 ± 45 g), independently of diet (P-sex <0.01). HFD led to a lower production of IL-2 while increasing the production of IL-10 (both P-diet ≤ 0.05), independently of sex. HFD-fed females had increased production of cytokines (IL-2 and IL-6) after stimulation with PMA+I, as well as a higher Th1:Th2 balance compared to HFD-fed males (all P <0.05). Males fed the HFD had significantly lower production of IL-2 upon stimulation compared to all other groups. Conclusion : Female Wistar rats developed a milder obesity phenotype and maintained enhanced cytokine production compared to males fed the HFD. Sex differences modulate immune function in the context of high-fat feeding and it should be considered in research design to establish personalized health-related recommendations.