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1.
Mol Cell Neurosci ; 95: 51-58, 2019 03.
Article in English | MEDLINE | ID: mdl-30660767

ABSTRACT

The ventromedial hypothalamic nucleus (VMN) is a critical component of the neural circuitry that regulates glucostasis. Astrocyte glycogen is a vital reserve of glucose and its oxidizable metabolite L-lactate. In hypoglycemic female rats, estradiol-dependent augmentation of VMN glycogen phosphorylase (GP) protein requires hindbrain catecholamine input. Research here investigated the premise that norepinephrine (NE) regulation of VMN astrocyte metabolism shapes local glucoregulatory neurotransmitter signaling in this sex. Estradiol-implanted ovariectomized rats were pretreated by intra-VMN administration of the monocarboxylate transporter inhibitor alpha-cyano-4-hydroxy-cinnamic acid (4CIN) or vehicle before NE delivery to that site. NE caused 4CIN-reversible reduction or augmentation of VMN glycogen synthase and phosphorylase expression. 4CIN prevented NE stimulation of gluco-inhibitory (glutamate decarboxylase65/67) and suppression of gluco-stimulatory (neuronal nitric oxide synthase) neuron marker proteins. These outcomes imply that effects of noradrenergic stimulation of VMN astrocyte glycogen depletion on glucoregulatory transmitter signaling may be mediated, in part, by glycogen-derived substrate fuel provision. NE control of astrocyte glycogen metabolism may involve down-regulated adrenoreceptor (AR), e.g. alpha1 and alpha2, alongside amplified beta1 AR and estrogen receptor-beta signaling. Noradrenergic hypoglycemia was refractory to 4CIN, implying that additional NE-sensitive VMN glucoregulatory neurochemicals may be insensitive to monocarboxylate uptake. Augmentation of circulating free fatty acids by combinatory NE and 4CIN, but not NE alone implies that acute hypoglycemia induced here is an insufficient stimulus for mobilization of these fuels, but is adequate when paired with diminished brain monocarboxylate fuel availability.


Subject(s)
Glucose/metabolism , Glycogen/metabolism , Monocarboxylic Acid Transporters/antagonists & inhibitors , Norepinephrine/pharmacology , Ventromedial Hypothalamic Nucleus/metabolism , Animals , Astrocytes/metabolism , Coumaric Acids/pharmacology , Enzyme Inhibitors/pharmacology , Estrogen Receptor beta/metabolism , Estrogens/deficiency , Fatty Acids/metabolism , Female , Glycogen Synthase/antagonists & inhibitors , Monocarboxylic Acid Transporters/metabolism , Norepinephrine/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic/metabolism , Ventromedial Hypothalamic Nucleus/cytology
2.
Neuropeptides ; 72: 65-74, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30396594

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 (ERß) 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 ERß 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 -ß enhance astrocyte AMPK and glycogen synthase expression and inhibit glycogen phosphorylase in hypoglycemic females, while ERß suppresses the same proteins in males. Differential VMN astrocyte protein responses to IIH may partially reflect ERα and -ß augmentation of ERß and down-regulation of alpha1, alpha2, and beta1 adrenoreceptor proteins in females, versus ERß 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 -ß are apparently uninvolved in these contra-regulatory responses.


Subject(s)
Astrocytes/metabolism , Glycogen/metabolism , Hypoglycemia/metabolism , Prosencephalon/metabolism , Receptors, Estrogen/metabolism , Sex Characteristics , Ventromedial Hypothalamic Nucleus/metabolism , Animals , Blood Glucose/metabolism , Female , Male , Neurons/metabolism , Ovariectomy , Rats , Rats, Sprague-Dawley
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