Central Responsiveness to a Ghrelin Mimetic (GHRP-6) is Rapidly Altered by Acute Changes in Nutritional Status in Rats

The hypothalamus appears to be more responsive to ghrelin and growth hormone secretagogues (GHS) in fasting, as reflected by a two‐ to three‐fold increase in the number of cells detected that express Fos protein in the arcuate nucleus, in 48‐h fasted rats compared to fed controls. Moreover, this increased hypothalamic responsiveness to GHS in fasting is regulated by the central action of exogenous leptin and insulin, although it is unknown whether these hormones mediate the changes in hypothalamic responsiveness to GHS associated with the fasting/fed state. In the present study, we show that refeeding with normal rat chow for only 2 h at the end of a 48‐h fast reversed the potentiation of the Fos response to GHRP‐6 observed in fasted rats. Circulating leptin and insulin levels remained significantly lower in refed rats compared to ad lib‐fed rats, suggesting that the change in the hypothalamic sensitivity brought about by refeeding was independent of these hormones. By contrast, 2 h of chow refeeding at the end of a fast restored plasma glucose levels to those of the fed state. Refeeding with sugar alone for 2 h at the end of a 48‐h fast also reduced the potentiated Fos response in fasting, indicating that elevated blood glucose can influence the central responsiveness to ghrelin/GHS. By contrast, infusion of the ileal satiety factor, PYY3‐36 (known to increase postprandially) did not alter the central responsiveness to GHRP‐6, although it suppressed feeding and body weight as expected. This study highlights the importance of nutritional status in regulating the action of exogenous GHS (and presumably endogenous ghrelin) on the hypothalamic circuits controlling food intake.