title: Inhibition of luteinizing hormone secretion and expression of c-fos and corticotrophin-releasing factor genes in the paraventricular nucleus during insulin-induced hypoglycaemia in sheep.
abstract: Insulin can act within the brain to stimulate ovine luteinizing hormone (LH) secretion, but insulin-induced hypoglycaemia inhibits LH via unknown brain sites, possibly involving corticotrophin-releasing factor (CRF). Castrate male sheep, with (E+) or without (E-) subcutaneous oestradiol implants, were blood sampled every 12 min for 8 h. Insulin (0.25 or 0.5 IU/kg) was injected at 4 h via the carotid artery or jugular vein. All treatments reduced LH output with no differences between dose rate nor route of administration, but sensitivity was greater in E+ than E-sheep. There was no evidence for an effect of insulin on LH 0-1 h postinjection; however, 1-3 h after insulin, when hypoglycaemia was established, LH pulses were inhibited in both E+ and E- sheep (P<0.001). Additional intravenous (i.v.) glucose injections given 1 h (20 mmol) and 2 h (10 mmol) after insulin (0.5 IU/kg) were each followed by an LH pulse within 30 min (75% response in both E+ and E-sheep). In a separate experiment, sheep were killed 2 h after i.v. insulin (0.5 IU/kg) or saline. In-situ hybridization revealed c-fos mRNA in the paraventricular nucleus (PVN), but not in any other hypothalamic nuclei nor in the hindbrain; and this was linked with increased CRF gene expression in the PVN. Similar c-fos and CRF gene expression was seen in insulin-treated sheep given additional i.v. glucose (20 and 10 mmol, respectively, 40 and 20 min ante mortem), but not in saline-treated controls. Therefore, insulin-induced hypoglycaemia inhibited LH secretion, with oestradiol potentiating the effect, and was associated with gonadal steroid-independent c-fos gene expression and increased CRF gene expression in the PVN. The ovine PVN may be involved in mediating insulin-induced hypoglycaemic inhibition of LH by a mechanism which might involve CRF.
authors.affiliation: Molecular Neuroendocrinology Unit, Rowett Research Institute, Bucksburn, Aberdeen, UK. cla@rri.sari.ac.uk
authors.forename: C L
authors.initials: CL
authors.lastname: Adam
authors.forename: P A
authors.initials: PA
authors.lastname: Findlay
mesh_terms: D000818:Animals; D001345:Autoradiography; D001786:Blood Glucose / Q000378:metabolism; D002339:Carotid Arteries; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D007003:Hypoglycemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D017403:In Situ Hybridization; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D007328:Insulin / Q000008:administration & dosage; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D015345:Oligonucleotide Probes; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012756:Sheep
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D015345:Oligonucleotide Probes; D016760:Proto-Oncogene Proteins c-fos; D007986:Luteinizing Hormone; D003346:Corticotropin-Releasing Hormone