Orexins, in addition to regulating food intake and playing a role in the sleep wake cycle, are involved in the activation of HPA axis. Starvation induces metabolic changes in the body, including upregulation of orexin and its receptors in the hypothalamus. We investigated the expression and signalling characteristics of rat orexin receptors at the hypothalamic and adrenal level in food deprived animals and controls. Food deprivation induced both orexin type-1 (OX1R) and type-2 (OX2R) receptor subtypes at mRNA and protein level in the hypothalamus; whereas in the adrenal cortex there was down regulation of these parameters. In this study we have demonstrated that orexin receptors can couple to multiple G proteins (Gs, Gi, Gq, Go) upon stimulation with orexin-A at the hypothalamic and adrenal level. In the hypothalamus, of food deprived rats, compared to controls, a significant increase in coupling of orexin receptors to Gq and Gs was demonstrated, whereas coupling to Gi was relatively less, and coupling to Go remained unchanged. However, in the adrenal cortex of the food-deprived animal there was decreased coupling of orexin receptors to Gs and Go, increased coupling to Gi, yet there was no coupling towards Gq. Subsequent second messenger studies using cAMP and 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.