Regulation of Growth Hormone Secretagogue Receptor Gene Expression in the Arcuate Nuclei of the Rat by Leptin and Ghrelin

Regulation of Growth Hormone Secretagogue Receptor Gene Expression in the Arcuate Nuclei of the Rat by Leptin and Ghrelin Ruben Nogueiras 1 , Sulay Tovar 1 , Sharon E. Mitchell 2 , D. Vernon Rayner 2 , Zoe A. Archer 2 , Carlos Dieguez 1 and Lynda M. Williams 2 1 Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain 2 Energy Balance and Obesity Division, Rowett Research Institute, Aberdeen, U.K Address correspondence and reprint requests to Lynda M. Williams, Energy Balance and Obesity Division, Rowett Research Institute, Aberdeen, AB21 9SB, U.K. E-mail: l.williams{at}rri.sari.ac.uk Abstract The anorexigenic and orexigenic hormones leptin and ghrelin act in opposition to one another. When leptin signaling is reduced, as in the Zucker fatty rat, or when circulating ghrelin is increased during fasting, the effect of ghrelin becomes more dominant, indicating an influence of both hormones on ghrelin action. This effect could be mediated via the level of expression of ghrelin receptor (growth hormone secretagogue receptor [GHS-R]). For testing this, GHS-R expression was measured using in situ hybridization in Zucker fatty versus lean rats; in fed versus fasted (48 h) rats, treated with either ghrelin or leptin; and in GH-deficient, dwarf versus control rats. In the arcuate nuclei of the Zucker fatty rat and in fasted rats, GHS-R expression is significantly increased. A single leptin intracerebroventricular injection attenuated the fasting-induced increase in GHS-R but had no effect in fed rats 2 h after injection, whereas leptin infusion for 24 h or longer significantly decreased GHS-R expression in fed rats. Ghrelin significantly increased GHS-R expression but not in dwarf rats. These results show that the level of GHS-R expression in the ARC is reduced by leptin and increased by ghrelin and that the effect of ghrelin may be GH dependent. AgRP, agouti gene–related protein ARC, arcuate nuclei CART, cocaine- and amphetamine-regulated transcript GH, growth hormone GHS-R, GH secretagogue receptor ICV, intracerebroventricular NPY, neuropeptide Y POMC, proopiomelanocortin VMN, ventromedial nuclei Footnotes Accepted July 2, 2004. Received March 24, 2004. DIABETES