Although starvation-induced biochemical and metabolic changes are perceived by the hypothalamus, the adrenal gland plays a key role in the integration of metabolic activity and energy balance, implicating feeding as a major synchronizer of rhythms in the hypothalamic-pituitary-adrenal (HPA) axis. Given that orexins are involved in the regulation of food intake and the activation of HPA axis, we hypothesized that food deprivation, an acute challenge to the systems that regulate energy balance, should elicit changes in orexin receptor signalling at the hypothalamic and adrenal level. Food deprivation induced both orexin type-1 (OX1R) and type-2 (OX2R) receptors at mRNA and protein level in the hypothalamus, in addition to a five-fold increase in prepro-orexin mRNA. Both cleaved peptides OR-A and OR-B are also elevated at the protein level. Interestingly, adrenal OX1R and OX2R levels were significantly reduced in food-deprived animals, whereas there was no expression of prepro-orexin in the adrenal gland in either state. Food deprivation exerted a differential effect on OXR-G protein coupling. In the hypothalamus, of food deprived rats, compared to controls, a significant increase in coupling of orexin receptors to Gq/11, Gs and Go was demonstrated, whereas coupling to Gi was relatively less. However, in the adrenal cortex of the food-deprived animal there was decreased coupling of orexin receptors to Gs, Go, and Gq/11 and increased coupling to Gi. Subsequent second messenger studies (cAMP/IP₃) have supported these findings. Our data indicate that food deprivation has differential effects on orexin receptor expression and their signalling characteristics at the hypothalamic and adreno-cortical level. These novel findings would suggest orexins as potential metabolic regulators within the HPA axis both centrally and peripherally.