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

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.

The objective was to determine sex differences on immune function in response to an HFD compared with a control low-fat diet (LFD) in Wistar rats.

At 5 wk of age, male and female Wistar rats were randomly assigned to 1 of 2 diets for 9 wk: 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 wk of age, rats were killed 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-factor ANOVA was used to assess the main effect of sex, diet, and their interaction.

Males gained more weight than females (410 ± 46 vs. 219 ± 45 g), independently of diet (P-sex < 0.01). The 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 phorbol 12-myristate 13-acetate plus ionomycin (PMA+I), as well as a higher T-helper (Th) 1:Th2 balance compared with HFD-fed males (all P < 0.05). Males fed the HFD had significantly lower production of IL-2 upon stimulation compared with all other groups.

Female Wistar rats developed a milder obesity phenotype and maintained enhanced cytokine production compared with 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.