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Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex

¹Biomedical Research Institute, Department of Biological Sciences, ²Warwick Medical School, University of Warwick, Coventry; and ³The Dean's Office, The Medical School, University of Leeds, Leeds, United Kingdom

Submitted 2 August 2004 ; accepted in final form 10 January 2005

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 regulating food intake and activating the HPA axis, we hypothesized that food deprivation, an acute challenge to the systems that regulate energy balance, should elicit changes in orexin receptor signaling at the hypothalamic and adrenal levels. Food deprivation induced orexin type 1 (OX1R) and 2 (OX2R) receptors at mRNA and protein levels in the hypothalamus, in addition to a fivefold increase in prepro-orexin mRNA. 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 with controls, a significant increase in coupling of orexin receptors to G_q, G_s, and G_o was demonstrated, whereas coupling to G_i was relatively less. However, in the adrenal cortex of the food-deprived animal, there was decreased coupling of orexin receptors to G_s, G_o, and G_q and increased coupling to G_i. 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 signaling characteristics at the hypothalamic and adrenocortical levels. These findings suggest orexins as potential metabolic regulators within the HPA axis both centrally and peripherally.

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