There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Central administration of the preproglucagon-derived peptide glucagon-like peptide-1
significantly inhibits ingestion of food and water, and glucagon-like peptide-1 binding
sites are present in a multitude of central areas involved in the regulation of ingestional
behaviour. To evaluate further the neuroanatomical organization of central glucagon-like
peptide-1 containing neuronal circuits with potential implications on ingestional
behaviour, we carried out a series of experiments in the rat demonstrating the topographical
sites of synthesis and processing of the preproglucagon precursor followed by a chromatographic
analysis of the processed fragments. In situ hybridization histochemistry revealed
that preproglucagon encoding messenger RNA was expressed in a single population of
neurons in the caudal portion of the nucleus of the solitary tract. Gel chromatographic
analysis of hypothalamic and brainstem tissue extracts revealed that the preproglucagon
precursor is processed in a fashion similar to that seen in the small intestine, preferentially
giving rise to glicentin, glucagon-like peptide-1 and glucagon-like peptide-2. This
single brain site of glucagon-like peptide-1 synthesis was subsequently confirmed
by immunohistochemical demonstration of glucagon-like peptide-1-immunoreactive perikarya
in the central and caudal parts of the nucleus of the solitary tract. Numerous sites
containing glucagon-like peptide-1 immunoreactive fibres were, however, discovered
in the forebrain including hypothalamic, thalamic and cortical areas. The densest
innervation by glucagon-like peptide-1 immunoreactive nerve fibres was seen in the
hypothalamic dorsomedial and paraventricular nuclei, but numerous glucagon-like peptide-1
immunoreactive fibres were also seen throughout the periventricular strata of the
third ventricle. Dual-labelling immunohistochemistry for tyrosine hydroxylase and
glucagon-like peptide-1 gave no evidence for co-localization of catecholamines and
glucagon-like peptide-1 in neurons of the lower brainstem. To identify neurons of
the nucleus of the solitary tract that project to the hypothalamic paraventricular
nucleus, the retrograde tracer FluoroGold was injected into this hypothalamic target
and dual immunocytochemical identification of glucagon-like peptide-1 and tyrosine
hydroxylase-positive neurons was performed on brainstem sections containing retrogradely
labelled perikarya. From this experiment it was seen that many of the retrogradely
labelled neurons in the central portion of the nucleus of the solitary tract are catecholaminergic,
while none is glucagon-like peptide-1 immunoreactive. In contrast, most of the retrogradely
labelled neurons of the caudal portion of the nucleus of the solitary tract contain
glucagon-like peptide-1. These observations further substantiate that glucagon-like
peptide-1 neurons of the solitary tract constitute a distinct non-catecholaminergic
cell group which projects to many targets, one of which is the hypothalamic paraventricular
nucleus.