Glucagon like peptide-1 (7-36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus

Abstract

Glucagon like peptide-1 (7-36) amide (GLP-1), a potent regulator of glucose homeostasis, is also produced in the central nervous system and has been implicated in the control of hypothalamic-pituitary function and food intake. GLP-1 immunoreactive (IR) fibers and terminals are widely distributed in the septum, hypothalamus, thalamus and brainstem, likely originating from GLP-1-IR neuronal cell bodies from the nucleus of the solitary tract of the medulla oblongata. Central administration of GLP-1 increases plasma corticosterone levels and elicits c-fos expression in corticotropin releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN). To identify the endogenous neurocircuitry that may underlie this response, the present study determined whether there is an innervation of PVN CRH neurons by GLP-1-containing nerve terminals. GLP-1-IR fibers and nerve terminals were found in the parvocellular parts of the PVN, with highest concentrations in the anterior and medial parvocellular subdivisions. The magnocellular divisions of the PVN also showed moderate numbers of GLP-1-IR nerve fibers. Double immunolabelling revealed numerous GLP-1-IR nerve fibers in close apposition to approximately 65% of detectable CRH neurons in the medial parvocellular subdivision of the rat PVN. At the ultrastructural level, GLP-1-IR terminals were observed to establish synapses on both perikarya and dendrites of CRH neurons. These findings support the hypothesis that the GLP-1-induced activation of CRH neurons and the associated pituitary-adrenocortical activation may be accomplished by GLP-1's direct action on hypophysiotropic CRH neurons. Since central CRH is also thought to be an anorexigenic factor and GLP-1 neurons contain leptin receptors, activation of CRH neurons in the PVN by GLP-1 may contribute to the complex neuroendocrine and metabolic actions by the adipostatic hormone, leptin.