Hypoglycemia differentially regulates hypothalamic glucoregulatory neurotransmitter gene and protein expression: role of caudal dorsomedial hindbrain catecholaminergic input

Abstract

The hypothalamic neurochemicals neuropeptide Y (NPY), orexin-A (ORX), and oxytocin (OXY) exert glucoregulatory effects upon intracerebral administration, findings that support their potential function within neural pathways that maintain glucostasis. Current understanding of how these neurotransmitter systems respond to the diabetes mellitus complication, insulin-induced hypoglycemia, is limited to knowledge of neuropeptide gene transcriptional reactivity. We investigated the hypothesis that hypoglycemia elicits hypothalamic site-specific alterations in levels of these neurochemicals, and that adjustments in local neurotransmitter availability may be regulated by catecholaminergic (CA) input from the caudal dorsomedial hindbrain. The arcuate (ARH) and paraventricular (PVH) hypothalamic nuclei and lateral hypothalamic area (LHA) were each microdissected from adult male rats pretreated by caudal fourth ventricular administration of the selective CA neurotoxin, 6-hydroxydopamine (6-OHDA), or vehicle prior to insulin (INS)-induced hypoglycemia. Hypoglycemia stimulated ARH NPY gene expression and NPY accumulation in the ARH and LHA, but not PVH. 6-OHDA pretreatment did not modify the positive NPY mRNA response to INS, but blunted hypoglycemic augmentation of ARH and LHA NPY content while increasing PVH NPY levels in response to hypoglycemia. INS-treated rats exhibited diminished LHA ORX gene expression and increased [ARH; LHA] or decreased [PVH] tissue ORX protein levels. 6-OHDA+INS animals showed a comparable decline in ORX transcripts, but attenuated augmentation of ARH and LHA ORX content and elevated PVH ORX levels. OT mRNA and protein were respectively decreased or unchanged during hypoglycemia, responses that were uninfluenced by hindbrain CA nerve cell destruction. These results illustrate divergent adjustments in glucoregulatory neurotransmitter gene expression and site-specific protein accumulation in the hypothalamus during hypoglycemia. Evidence that 6-OHDA pretreatment does not modify NPY or ORX transcriptional reactivity to hypoglycemia, but alters hypoglycemic patterns of NPY and ORX accretion implicates dorsomedial hindbrain CA neurons in regulation of translation/post-translational processing and site-specific availability of these neurotransmitters in the hypothalamus during hypoglycemia.