Growth hormone secretagogues and hypothalamic networks.

Growth hormone secretagogues (GHSs) act at distinct levels to control growth hormone (GH) secretion. At the pituitary level they reinforce or extend a tonic GH-releasing-hormone (GHRH)-induced activated state by mobilizing intracellular Ca2+ store. At the hypothalamic level GHS actions are more complex than originally anticipated. Chronic treatments with GHS result in loss of responsiveness to the secretagogues, an effect probably accounted for by indirect negative feedback of GHS stimulated plasma GH levels over GHRH release. Moreover, intracerebroventricular treatments with GHS can have paradoxical, inhibitory effects on GH secretion. Several mechanisms can account for such dual effects. GHS receptors were found to extend far beyond the arcuate nucleus and are mainly coexpressed by GHRH, somatostatin, and neuropeptide Y (NPY) neurons. Activation of GHRH neurons by GHS can be direct or indirect. Indeed using antisense strategy we found that sstl are physiological activators of arcuate GHRH neurons and we propose that activation of SRIH arcuate interneurons by GHS can increase GHRH neuron activity. Moreover, GHS can stimulate distinct populations of NPY neurons having opposite effects on GH secretion: arcuate NPY interneurons, act as indirect facilitators of GHRH release, whereas, on the contrary, a different subset of NPY neurons projecting to the periventricular hypothalamus (those also involved in mediating leptin effects on GH) seems able to activate SRIH release.