Sex-dimorphic growth hormone-releasing hormone (Ghrh) receptor regulation of ventromedial hypothalamic nucleus Ghrh neuron estrogen receptor variant gene expression.

Abstract

Estradiol shapes systemic glucose homeostasis by action on ventromedial hypothalamic nucleus (VMN) targets. The neuropeptide transmitter growth hormone-releasing hormone (Ghrh) governs counterregulatory neurochemical marker mRNA expression in dorsomedial VMN (VMNdm) Ghrh/steroidogenic factor-1 (SF-1/Nr5a1) neurons. The current research used tools for in vivo gene silencing and single-cell laser catapult microdissection/multiplex qPCR to determine if VMN Ghrh receptor (Ghrh-R) regulates nuclear and/or membrane estrogen receptor (ER) gene transcription in those neurons. Intra-VMN Ghrh-R siRNA correspondingly up- or down-regulated baseline VMNdm Ghrh/SF-1 neuron ER-alpha (ERα) or G protein-coupled estrogen receptor-1 (GPER) transcripts in male rats; neither mRNA was affected by gene silencing in females. In each sex, hypoglycemic repression of these ER gene profiles was averted by Ghrh-R gene knockdown. Both sexes exhibited diminished baseline VMNdm Ghrh/SF-1 neuron ER-beta (ERβ) gene expression following Ghrh-R gene knockdown. ERβ mRNA was diminished (male) or unaffected (female) by hypoglycemia; Ghrh-R siRNA pretreatment enhanced transcript levels in hypoglycemic rats of either sex. Aromatase gene expression is higher in male versus female VMNdm Ghrh/SF-1 neurons and is inhibited by hypoglycemia in male rats alone. Ghrh-R gene knockdown augmented aromatase mRNA levels in each sex irrespective of glucose status. Results document glucose-dependent Ghrh-R control of VMNdm Ghrh/SF-1 neuron ERα (female), ERβ (both sexes), and GPER (both sexes) gene expression. Ongoing studies aim to characterize mechanisms that cause a hypoglycemia-associated gain of regulatory control or switch in direction (stimulatory-to-inhibitory) of control. Outcomes identify VMNdm Ghrh/SF-1 neurons as a putative neuroestradiol source in each sex and implicate Ghrh-R in hypoglycemic repression of this neurosteroid profile in males.