Genistein Enhances Female Survival and Promotes Male Weight Gain in ΔF508-CF Mice Through Sex-Dependent Intestinal and Hepatic Mechanisms

Background: ∆F508 cystic fibrosis (CF) mice exhibit severe intestinal disease and require constant Colyte laxative treatment for survival. We previously demonstrated that dietary supplementation with genistein, a phytoestrogenic isoflavone, improved survival rates in females and increased weight gain in males. The goal of this study was to determine the mechanisms underlying these effects. Methods: Male and female ∆F508 mice were randomly assigned to one of three groups and fed the corresponding diet for 45 days (starting at day 20): 600 mg genistein/kg of food (Gen), standard diet without Colyte (Std), or standard diet with Colyte (Col). Liver samples were analyzed for key genes or proteins involved in metabolism; serum samples were assayed for glucose, GIP, and insulin; and jejunum samples were assessed for cytokines and genes involved in intestinal health. Results: The genistein diet significantly increased serum glucose levels and jejunum levels of the cytokines IL-17A, IL-4, and IL-5 in both male and female mice compared to the Colyte-fed group. In females, the jejunum levels of the cytokines LIX and Il-7 decreased compared to Colyte-fed mice, and in males, MIP-2 and KC levels increased compared to Colyte-fed mice. Jejunum gene expression levels of TRPv6, MUC2, and ER-α all significantly increased in females, but not in males. Hepatic levels of GLUT4 protein decreased in males and females fed the genistein diet versus those fed Colyte, which was accompanied by an increase in 11β-HSD, corticosteroid-binding globulin, glucocorticoid receptor, and FAS in females, but only an increase in FAS was observed in males. Conclusions: The genistein-induced increase in survival rates of female ΔF508-CF mice can be attributed to the following mechanisms: decreased levels of LIX and Il-7, increased gluconeogenesis and de novo lipogenesis, and increased intestinal TRPv6, MUC2, and ER-α gene expression. Furthermore, the increased weight gain without an improvement in survival in male ΔF508-CF mice on the genistein diet can be attributed in part to increased de novo lipogenesis. Further studies could elaborate on additional cellular mechanisms.