A high cholesterol diet elevates hippocampal cytokine expression in an age and estrogen-dependent manner in female rats.
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BACKGROUND: While the effects of a proatherogenic diet have been widely studied in the context of systemic inflammation, much less is known about its effects on central or brain inflammation and its modulation with age. In this study, we examined the effect of a high cholesterol/choline diet in adult and older acyclic females to assess its impact on systemic and central inflammatory markers. Moreover, since the loss of ovarian hormones at menopause may predispose women to increased production of pro-inflammatory cytokines, we also tested the impact of estrogen replacement to adult and older females in diet-induced inflammation. METHODS: Ovariectomized adult female rats and older (reproductive senescent) female rats were replaced with estrogen or a control pellet and maintained thereafter on a diet containing either 4% cholesterol/1% choline or control chow for 10 weeks. Interleukin 1beta (IL-1beta) expression in the liver was used as a marker of systemic inflammation, while a panel of cytokine/chemokines were used to examine the effects of diet on the hippocampus. RESULTS: IL-1beta expression was elevated in the liver of adult and reproductive senescent females fed with the high cholesterol diet, although this was restricted to groups that were ovariectomized and not replaced with estrogen. Estrogen-treated animals of both ages did not have elevated IL-1beta levels when fed the high cholesterol diet. Diet-induced changes in cytokine/chemokine expression in the hippocampus however were critically age dependent and restricted to the reproductive senescent females. In this group, the high cholesterol diet led to an increase in interleukin (IL)-4, IL-6, IL-12p70, IL-13, RANTES (Regulated on Activation, Normal T Expressed and Secreted) and VEGF (vascular endothelial growth factor). Moreover, estrogen treatment to reproductive senescent females suppressed diet-induced expression of specific cytokines (RANTES, VEGF, IL-6) and attenuated the expression of others (IL-4, IL-12p70, and IL-13). CONCLUSIONS: These data indicate that a proatherogenic diet presents a significant risk for central inflammation in older females that are deprived of estrogen treatment.
