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. 2018 Dec:72:65-74.
doi: 10.1016/j.npep.2018.10.003. Epub 2018 Oct 26.

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

A S M Hasan Mahmood  1 , M M Uddin  1 , M M H Ibrahim  1 , S K Mandal  1 , H N Alhamami  1 , K P Briski  2
Affiliations

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

A S M Hasan Mahmood et al. Neuropeptides. 2018 Dec.

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.

Keywords: 5-adenosine monophosphate-activated protein kinase; Estrogen receptor; Glucagon; Glycogen synthase; Neuronal nitric oxide synthase; Ventromedial hypothalamic nucleus.

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Figures

Figure 1.
Figure 1.. Effects of Lateral Ventricular (LV) Pretreatment of the 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) on Ventromedial Hypothalamic Nucleus (VMN) Metabolic Neurotransmitter Marker Protein Responses to Insulin-Induced Hypoglycemia (IIH) in Female Versus Male Rats.
Micropunch-dissected VMN tissue was obtained from groups of estradiol (E) – implanted ovariectomized (OVX) female and testes-intact male rats pretreated by LV administration of MPP, PHTPP, or vehicle prior to sc insulin (INS) injection for Western blot analysis of glutamate decarboxylase65/67 (GAD65/67) [Panel A; female data at left, male data at right], neuronal nitric oxide synthase (nNOS) [Panel B; female data at left, male data at right], steroidogenic factor-1 (SF-1) [Panel C; female data at left, male data at right], and brain-derived neurotrophic factor (BDNF) [Panel D; female data at left, male data at right] expression. Data depict for each sex mean normalized protein optical density (O.D.) values ± S.E.M. for vehicle-pretreated animals injected sc with vehicle-(solid white bars; n=6) or INS (solid gray bars; n=6) or INS-injected rats pretreated with MPP (diagonal-striped gray bars; n=6) or PHTPP (cross-hatched gray bars; n=6). *p<0.05; **p<0.01; **p<0.001.
Figure 2.
Figure 2.. Effects of MPP or PHTPP Pretreatment on VMN Glycogen Metabolic Enzyme and Cell Type-Specific Monocarboxlyate Transporter Protein Expression in Hypoglycemic Female and Male Rats.
Data show for OVX + E female and testes-intact male rats mean normalized VMN glycogen synthase (GS) [Panel A; female data at left, male data at right], glycogen phosphorylase (GP) [Panel B; female data at left, male data at right], astrocytic monocarboxylate transporter-1 (MCT1) [Panel C; female data at left, male data at right], and neuronal monocarboxylate transporter-2 (MCT2) [Panel D, female data at left, male data at right] protein O.D. measures ± S.E.M. for treatment groups consisting of vehicle-pretreated eu-and hypoglycemic rats and ER antagonist-pretreated hypoglycemic animals. *p<0.05; **p<0.01; **p<0.001.
Figure 3.
Figure 3.. Effects of MPP or PHTPP Pretreatment on VMN Astrocyte 5’-AMP-Activated Protein Kinase (AMPK) and Phospho-AMPK (pAMPK) Protein Content in Hypoglycemic Female and Male Rats.
Glial fibrillary acidic protein (GFAP)-immunopositive astrocytes were laser-microdissected from the VMN of vehicle-pretreated eu-(solid white bars) and hypoglycemic (solid gray bars) animals and MPP-(diagonal-striped bars) or PHTPP (cross-hatched gray bars)-pretreated INS-injected rats for Western blot analysis of AMPK [Panel A; female data at left, male data at right] and pAMPK [Panel B; female data at left, male data at right] protein expression. Data illustrate for each sex mean normalized astrocyte protein O.D. measures ± S.E.M. for each treatment group. *p<0.05; **p<0.01; **p<0.001.
Figure 4.
Figure 4.. Effects of MPP versus PHTPP on VMN Astrocyte Estrogen Receptor (ER)-Alpha (ERα), ER-Beta (ERβ), and G Protein-Coupled Estrogen Receptor (GPER) Protein Expression in Hypoglycemic Female and Male Rats.
VMN astrocyte lysates were evaluated by Western blot for ERα [Panel A; female data at left, male data at right], ERβ [Panel B; female data at left, male data at right], and GPER [Panel C; female data at left, male data at right] protein expression in groups of vehicle-pretreated eu-(solid white bars) and hypoglycemic (solid gray bars) animals and MPP-(diagonal-striped bars) or PHTPP (cross-hatched gray bars)-pretreated INS-injected rats. Data depict for each sex mean normalized astrocyte protein O.D. measures ± S.E.M. for each treatment group. *p<0.05; **p<0.01; **p<0.001.
Figure 5.
Figure 5.. Effects of MPP versus PHTPP on VMN Astrocyte Alpha1-Adrenergic Receptor (α1AR), Alpha2-AR (α2AR), and Beta1-AR (β1AR) Protein Expression in Hypoglycemic Female and Male Rats.
VMN astrocyte lysates were evaluated by Western blot for α1AR [Panel A; female data at left, male data at right], α2AR [Panel B; female data at left, male data at right], and β1AR [Panel C; female data at left, male data at right] protein expression in groups of vehicle-pretreated eu-(solid white bars) and hypoglycemic (solid gray bars) animals and MPP-(diagonal-striped bars) or PHTPP (cross-hatched gray bars)-pretreated INS-injected rats. Data depict for each sex mean normalized astrocyte protein O.D. measures ± S.E.M. for each treatment group. *p<0.05; **p<0.01; **p<0.001.
Figure 6.
Figure 6.. Impact of MPP or PHTPP Pretreatment on Insulin-Induced Hypoglycemia and Counter-Regulatory Hormone Secretion in Female versus Male Rats.
Data show circulating glucose [Panel A; female data at left, male data at right], glucagon [Panel B; female data at left, male data at right], and corticosterone [Panel C; female data at left, male data at right] levels in groups of groups of vehicle-pretreated eu-(solid white bars) and hypoglycemic (solid gray bars) animals and MPP-(diagonal-striped bars) or PHTPP (cross-hatched gray bars)-pretreated INS-injected rats. Bars depict for each sex mean concentrations ± S.E.M. for each treatment group.
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