Adaptation of Arcuate Insulin Receptor, Estrogen Receptor-Alpha, Estrogen Receptor-Beta, and Type-II Glucocorticoid Receptor Gene Profiles to Chronic Intermediate Insulin-Induced Hypoglycemia in Estrogen-Treated Ovariectomized Female Rats

作者：Genabai Naresh K; Briski Karen P^*

来源：Journal of Molecular Neuroscience, 2010, 41(2): 304-309.

DOI：10.1007/s12031-009-9314-4

• Ovariectomy
• Estradiol benzoate
• Arcuate nucleus
• Neutral protamine Hagedorn insulin
• Insulin receptor
• Estrogen receptor-alpha
• Estrogen receptor-beta
• Type-II glucocorticoid receptor

Insulin and corticosterone signal energy surfeit and deficiency, respectively, to metabolic structures in the brain, including the hypothalamic arcuate nucleus (ARH). This peripheral input may be subject to ovarian control, since ovariectomy (OVX) increases insulin receptor transcripts and decreases glucocorticoid receptor protein in the hypothalamus. The present studies examined the hypothesis that estradiol regulates basal and hypoglycemic patterns of ARH insulin and glucocorticoid receptor mRNA expression, and governs habituation of these gene profiles to recurring intermediate insulin administration. The premise that estrogen receptor-alpha (ER alpha) and beta (ER beta) gene profiles may be regulated differentially during acute and chronic hypoglycemia in the presence of estradiol was also evaluated. Insulin receptor-beta chain (InsRb), type-II glucocorticoid receptor (GR), ER alpha, and ER beta mRNA levels in ARH tissue microdissected from estradiol benzoate (EB)- and oil-implanted OVX rats after single or serial sc neutral protamine Hagedorn insulin (NPH) injection were measured by quantitative real-time RT-PCR. ARH InsRb gene profiles were decreased, relative to baseline, after either one or four NPH injections in OVX EB rats; mean mRNA levels were significantly lower after serial dosing since basal InsRb transcripts were diminished by precedent NPH treatment. InsRb transcription rates did not differ among OVX oil treatment groups. Acute insulin elevated ARH GR mRNA relative to baseline in both EB- and oil-implanted rats. Prior NPH injections increased basal GR gene expression and suppressed transcriptional reactivity to a fourth dose of NPH in OVX EB, but not OVX oil animals. ARH ER alpha and ER beta mRNA levels were increased or decreased, respectively, after one insulin dose in OVX EB rats. Baseline expression of these genes was correspondingly augmented or suppressed after precedent NPH treatment, but ER alpha and ER beta transcripts were not modified relative to these adjusted baselines after a fourth NPH dose. In the presence of estradiol, ARH InsRb and GR gene profiles exhibit divergent modifications during acute NPH-induced hypoglycemia, as well as opposite adjustments in baseline expression after serial NPH dosing. GR transcriptional acclimation to recurring NPH administration was also estrogen-dependent. Further research is needed to characterize potential effects of adjustments in ARH neuronal sensitivity to insulin and corticosterone on ARH metabolic neurotransmitter release during and after intermediate insulin-induced hypoglycemia in females. The current evidence for converse effects of NPH on ARH ER alpha and ER beta gene profiles in the presence of estradiol supports the need to identify ARH-directed metabolic activities governed by each ER subtype, including metabolic hormone receptor expression, and to assess the impact of NPH-induced habituation of ER gene profiles on those functions.

• 出版日期2010-6