Shiftworkers run an increased risk of developing metabolic disorders, presumably as a result of disturbed circadian physiology. Eating at a time-of-day that is normally dedicated to resting and fasting, may contribute to this association. The hypothalamus is the key brain area that integrates different inputs, including environmental time information from the central biological clock in the suprachiasmatic nuclei, with peripheral information on energy status to maintain energy homeostasis. The orexin system within the lateral hypothalamus is an important output of the suprachiasmatic nuclei involved in the control of sleep/wake behavior and glucose homeostasis, among other functions. In this study, we tested the hypothesis that feeding during the rest period disturbs the orexin system as a possible underlying contributor to metabolic health problems. Male Wistar rats were exposed to an 8-week protocol in which food was available ad libitum for 24-hours, for 12-hours during the light phase (i.e., unnatural feeding time) or for 12-hours during the dark phase (i.e., restricted feeding, but at the natural time-of-day). Animals forced to eat at an unnatural time, i.e. during the light period, showed no changes in orexin and orexin-receptor gene expression in the hypothalamus, but the rhythmic expression of clock genes in the lateral hypothalamus was absent in these animals. Light fed animals did show adverse changes in whole body physiology and internal desynchronization of muscle and liver clock and metabolic gene expression. Eating at the 'wrong' time-of-day thus causes internal desynchronization at different levels, which in the long run may disrupt body physiology. This article is protected by copyright. All rights reserved.