The farnesoid X receptor (FXR) has been suggested to play a role in gluconeogenesis. To determine whether FXR modulates the response to fasting in vivo, FXR-deficient (FXR-/-) and wild-type mice were submitted to fasting for 48 h. Our results demonstrate that FXR modulates the kinetics of alterations of glucose homeostasis during fasting, with FXR-/- mice displaying an early, accelerated hypoglycaemia response. Basal hepatic glucose production rate was lower in FXR-/- mice, together with a decrease in hepatic glycogen content. Moreover, hepatic PEPCK gene expression was transient lower in FXR(-/-)mice after 6 h of fasting and was decreased in FXR(-/-)hepatocytes. FXR therefore plays an unexpected role in the control of fuel availability upon fasting. (c) 2005 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.