Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling

OBJECTIVE: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R(−/−) animals. METHODS: We studied female mice with a global deletion of the α isoform of the IL-18 receptor (IL-18R(−/−)) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. RESULTS: Female IL-18R(−/−) mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R(−/−) mice was lost with aging. By 72 weeks of age, IL-18R(−/−) mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R(−/−) mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. CONCLUSIONS: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R(−/−) mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R(−/−) mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment.