Sex differences in forebrain estrogen receptor regulation of hypoglycemic patterns of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and astrocyte glycogen metabolic enzyme expression

Abstract

The female ventromedial hypothalamic nucleus (VMN) is a focal substrate for estradiol (E) regulation of energy balance, feeding, and body weight, but how E shapes VMN gluco-regulatory signaling in each sex is unclear. This study investigated the hypothesis that estrogen receptor-alpha (ERα) and/or -beta (ERβ) control VMN signals that inhibit [γ-aminobutyric acid] or stimulate [nitric oxide, steroidogenic factor-1 (SF-1)] counter-regulation in a sex-dependent manner. VMN nitrergic neurons monitor astrocyte fuel provision; here, we examined how these ER regulate astrocyte glycogen metabolic enzyme, monocarboxylate transporter, and adrenoreceptor protein responses to insulin-induced hypoglycemia (IIH) in each sex. Testes-intact male and E-replaced ovariectomized female rats were pretreated by intracerebroventricular ERα antagonist (MPP) or ERβ antagonist (PHTPP) administration before IIH. Data implicate both ER in hypoglycemic inhibition of neuronal nitric oxide synthase protein in each sex and up-regulation of glutamate decarboxylase65/67 and SF-1 expression in females. ERα and -β enhance astrocyte AMPK and glycogen synthase expression and inhibit glycogen phosphorylase in hypoglycemic females, while ERβ suppresses the same proteins in males. Differential VMN astrocyte protein responses to IIH may partially reflect ERα and -β augmentation of ERβ and down-regulation of alpha1, alpha2, and beta1 adrenoreceptor proteins in females, versus ERβ repression of GPER and alpha2 adrenoreceptor profiles in males. MPP or PHTPP pretreatment blunted counter-regulatory hormone secretion in hypoglycemic males only, suggesting that in males one or more VMN neurotransmitters exhibiting sensitivity to forebrain ER may passively regulate this endocrine outflow, whereas female forebrain ERα and -β are apparently uninvolved in these contra-regulatory responses.

Norepinephrine Regulation of Ventromedial Hypothalamic Nucleus Metabolic-Sensory Neuron 5′-AMP-Activated Protein Kinase Activity: Impact of Estradiol

“…These outcomes provide novel proof of a hindbrain catecholamine-reliant activation of VMN astrocyte AMPK by hypoglycemia in the presence of estrogen. Additional studies corroborate these findings with proof that hypoglycemia stimulates VMN astrocyte AMPK and pAMPK profiles in female, but not male rats, and that these sex-dimorphic sensor activity responses are mediated by ERs [30]. Data reported by Ibrahim et al [24] show that AMPK is involved in the NE regulation of VMN astrocyte expression of plasma membrane estrogen receptor GPER and β 1 -AR protein expression, as well as in GS and GP profiles.…”

“…The VMN is also a plausible site of the estrogenic control of glucostasis as the local administration of estradiol alters insulin-induced hypoglycemia in OVX female rats [29]. Documented effects of the intracerebroventricular (icv) delivery of ERα antagonist 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) or ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) implicate these estrogen receptors (ERs) in forebrain mechanisms that govern VMN nNOS and GAD 65/67 protein responses to hypoglycemia [30].…”

“…These data uniquely demonstrate ER-dependent NE control of VMN GP variant expression. In light of proof that VMN astrocytes express these ERs and α 1 -AR, α 2 -AR, and β 1 -AR proteins, and that hypoglycemic patterns of AR variant expression are controlled by ERs [30], it is plausible that estradiol and NE signals may interact within these glia to direct physiological stimulus-specific control of glycogen mobilization (Figure 1).…”

Estrogen Receptor Involvement in Noradrenergic Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neurotransmitter and Stimulus-Specific Glycogen Phosphorylase Enzyme Isoform Expression

“…The VMN is a target of estrogen control of glucose homeostasis as hormone delivery to that structure alters insulin-induced hypoglycemia in ovariectomized (OVX) female rats (Nedungadi and Briski, 2012). Intracerebroventricular effects of the estrogen receptor-alpha (ERα) antagonist 1,3- Bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1 H -pyrazole dihydrochloride (MPP) or ER-beta (ERβ) antagonist 4-[2-phenyl-5,7- bis (trifluoromethyl)pyrazolo[1,5- a ]pyrimidin-3-yl]phenol (PHTPP) implicate these ERs in hypoglycemic suppression of VMN nNOS and augmentation of GAD 65/67 profiles in females (Mahmood et al., 2018). NO and GABA neurons are plausible substrates for estradiol action as both cell types express ERα, ERβ, and the transmembrane G protein-coupled estrogen receptor (GPER)/G protein-coupled receptor 30 proteins (Uddin et al., 2019).…”

“…Our studies also show that hindbrain A2 noradrenergic lactoprivic signaling exerts opposite effects on VMN GPbb versus GPmm profiles in vivo (Briski and Mandal, 2019). Although female rat VMN astrocytes are directly sensitive to estradiol by virtue of ER expression (Mahmood et al., 2018, 2019), involvement of these ERs in noradrenergic regulation of GP isoforms is unclear. Current studies addressed the premise that VMN ERα and/or ERβ signaling may shape differential effects of NE on VMN GPbb versus GPmm protein expression and that ER control of glycogen metabolic enzyme profiles may correlate with observed noradrenergic regulation of nNOS or GAD.…”