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.
In the course of a COVID-19 pandemic, 0.33 million people got infected in Bangladesh, we made the first and successful attempt to detect SARS-CoV-2 viruses' genetic material in the vicinity wastewaters of an isolation centre i.e. Shaheed Bhulu Stadium, situated at Noakhali. The idea was to understand the genetic loading variation, both temporal and distance-wise in the nearby wastewater drains when the number of infected COVID-19 patients is not varying much. Owing to the fact that isolation center, in general, always contained a constant number of 200 COVID-19 patients, the prime objective of the study was to check if several drains carrying RNA of coronavirus are actually getting diluted or accumulated along with the sewage network. Our finding suggested that while the temporal variation of the genetic load decreased in small drains over the span of 50 days, the main sewer exhibited accumulation of SARS-CoV-2 RNA. Other interesting finding displays that probably distance of sampling location in meters is not likely to have a significant impact on gene detection concentration, although the quantity of the RNA extracted in the downstream of the drain was higher. These findings are of immense value from the perspective of wastewater surveillance of COVID-19, as they largely imply that we do not need to monitor every wastewater system, and probably major drains monitoring may illustrate the city health. Perhaps, we are reporting the accumulation of SARS-CoV-2 genetic material along with the sewer network i.e. from primary to tertiary drains. The study sought further data collection in this line to simulate conditions prevailed in the most of south Asian country and to shed further light on the temporal variation and decay/accumulation processes of the genetic load of the SARS-COV-2.
Estrogen receptor-alpha (ERα) and -beta (ERβ) occur in key elements of the brain glucohomeostatic network in both sexes, including the hindbrain dorsal vagal complex (DVC), but the influence of distinct receptor populations on this critical function is unclear. The ventromedial hypothalamic nucleus (VMN) maintains glucose balance by integrating nutrient, endocrine, and neurochemical cues, including metabolic sensory information supplied by DVC A2 noradrenergic neurons. Current research utilized the selective ERα and ERβ antagonists MPP and PHTPP to characterize effects of DVC ERs on VMN norepinephrine (NE) activity and metabolic neurotransmitter signaling in insulin-induced hypoglycemic (IIH) male rats. Data show that ERβ inhibits VMN glycogen synthase and stimulates phosphorylase protein expression, while attenuating hypoglycemic augmentation of glycogen content. Furthermore, both ERs attenuate VMN glucose concentrations during IIH. Hypoglycemic up-regulation of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) signaling was correspondingly driven by ERα or -β, whereas GABA and steroidogenic factor-1 were respectively suppressed independently of ER input or by ERβ. IIH intensified VMN NE accumulation by ERβ-dependent mechanisms, but did not alter NE levels in other gluco-regulatory loci. ERβ amplified the magnitude of insulin-induced decline in blood glucose. Both ER regulate corticosterone, but not glucagon secretion during IIH and oppose hypoglycemic diminution of circulating free fatty acids. These findings identify distinguishing versus common VMN functions targeted by DVC ERα and -β. Sex differences in hypoglycemic VMN NE accumulation, glycogen metabolism, and transmitter signaling may involve, in part, discrepant regulatory involvement or differential magnitude of impact of these hindbrain ERs.
Background
Ventromedial hypothalamic nucleus (VMN) gluco-regulatory transmission is subject to sex-specific control by estradiol. The VMN is characterized by high levels of aromatase expression.
Methods
The aromatase inhibitor letrozole (LZ) was used with high-resolution microdissection/Western blot techniques to address the hypothesis that neuroestradiol exerts sex-dimorphic control of VMN neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase65/67 (GAD) protein expression. Glycogen metabolism impacts VMN nNOS and GAD profiles; here, LZ treatment effects on VMN glycogen synthase (GS) and phosphorylase brain- (GPbb; glucoprivic-sensitive) and muscle (GPmm; norepinephrine-sensitive) variant proteins were examined.
Results
VMN aromatase protein content was similar between sexes. Intracerebroventricular LZ infusion of testes-intact male and ovariectomized, estradiol-replaced female rats blocked insulin-induced hypoglycemic (IIH) up-regulation of this profile. LZ exerted sex-contingent effects on basal VMN nNOS and GAD expression, but blocked IIH-induced NO stimulation and GAD suppression in each sex. Sex-contingent LZ effects on basal and hypoglycemic patterns of GPbb and GPmm expression occurred at distinctive levels of the VMN. LZ correspondingly down- or up-regulated baseline pyruvate recycling pathway marker protein expression in males (glutaminase) and females (malic enzyme-1), and altered INS effects on those proteins.
Conclusions
Results infer that neuroestradiol is required in each sex for optimal VMN metabolic transmitter signaling of hypoglycemic energy deficiency. Sex differences in VMN GP variant protein levels and sensitivity to aromatase may correlate with sex-dimorphic glycogen mobilization during this metabolic stress. Neuroestradiol may also exert sex-specific effects on glucogenic amino acid energy yield by actions on distinctive enzyme targets in each sex.
The VMN functions within the neural glucostatic network. Estradiol exerts sex‐specific control of VMN nitric oxide (NO) and γ‐aminobutyric acid (GABA) transmission, which respectively stimulates or suppresses glucose counter‐regulatory hormone secretion. In the brain, the VMN is a principal site of neuroestradiol production by aromatase. This project utilized the aromatase inhibitor letrozole (LZ) alongside combinatory high‐resolution microdissection/Western blotting to address the premise that neuroestradiol governance of VMN metabolic sensory neuron protein marker [neuronal nitric oxide synthase (nNOS); glutamate decarboxylase65/67 (GAD)] expression is sex‐dimorphic. Glycogen metabolism impacts VMN nNOS and GAD profiles; here, LZ treatment effects on VMN glycogen synthase (GS) and phosphorylase brain‐ (GPBB; glucoprivic‐sensitive) and muscle (GPMM; norepinephrine‐sensitive) variant proteins were examined. VMN aromatase protein content was equivalent between the sexes; intracerebroventricular LZ infusion of testes‐intact male and ovariectomized, estradiol‐replaced female rats blocked insulin (INS)‐induced hypoglycemia up‐regulation of this profile. LZ elicited sex‐contingent changes in basal VMN nNOS and GAD expression, but blocked INS‐induced NO stimulation and GAD suppression in each sex. INS caused LZ‐reversible GPBB augmentation or suppression in male versus female, respectively. Male and female VMN GPMM content was correspondingly unchanged or decreased by INS; LZ reduced baseline GPMM expression in females only, but did not attenuate INS regulation in either sex. LZ correspondingly down‐ or up‐regulated baseline pyruvate recycling pathway marker protein expression in males (glutaminase) and females (malic enzyme‐1), and altered INS effects on the same proteins. Results show that neuroestradiol is required in each sex for optimal VMN metabolic transmitter signaling of hypoglycemia‐associated energy deficiency. Locally‐generated estradiol steroid involvement in sex‐specific hypoglycemic patterns of VMN glucoprivic‐sensitive GPBB expression may correlate with sex‐dimorphic glycogen mobilization during this metabolic stress. Neuroestradiol may also exert sex‐specific effects on glucogenic amino acid energy yield by actions on distinctive enzyme targets in each sex.
Support or Funding Information
National Institutes of Health DK‐109382
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