The time course of the action of food deprivation on the functional activation of corticotropin-releasing hormone (CRH) neurons and on the expression of the genes encoding CRH and its receptors of type 1 (CRH1-R) and 2alpha (CRH2-R) in the brain were assessed in lean (Fa/?) and obese (fa/fa) Zucker rats. Fa/? and fa/fa rats were assigned to food deprivation periods of 0, 3, 6, 12, and 24 h. Measurements of Fos immunoreactivity and CRH mRNA were carried out on the same brain sections to assess the state of activation of CRH neurons. In situ hybridization histochemistry was employed to measure the mRNAs encoding CRH and its receptors. In fa/fa rats, food deprivation induced a rapid expression of Fos in CRH cells of several brain regions that include the paraventricular hypothalamic nucleus (PVN), the bed nucleus of the stria terminalis (BNST), the anterodorsal preoptic nucleus, the medial preoptic nucleus, the substantia innominata and Barrington's nucleus. The colocalization of Fos immunoreactivity and CRH mRNA was particularly noticeable in the PVN of fa/fa rats, where the majority of the CRH cells of the parvocellular division of the nucleus displayed Fos-positive nuclei, 12 h after the onset of fasting. In obese rats, food deprivation also produced an increase in the CRH mRNA levels in the BNST as well as high and low expressions of the CRH1-R in, respectively, the PVN and the anterior lobe of the pituitary. The expression of CRH1-R in the PVN of obese rats occurred 12 h after the onset of the deprivation. In Fa/? rats, food deprivation induced no marked activation of the CRH cells, a slow decrease in the CRH mRNA levels in the BNST and the central nucleus of the amygdala, and a gradual decrease in the expression of CRH2-R gene in the ventromedial hypothalamic nucleus. These results demonstrate that food deprivation is capable of generating in obese Zucker rats a stress-like response that translates into a particularly striking activation of the hypothalamic-pituitary-adrenal axis. This response contrasts with that observed in Fa/? rats, in which the action of food deprivation on the CRH system seems more compatible with the known effects of CRH in the regulation of energy balance.