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. 2019 Mar:95:51-58.
doi: 10.1016/j.mcn.2019.01.004. Epub 2019 Jan 17.

Norepinephrine control of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter expression in the female rat: Role of monocarboxylate transporter function

A S M Hasan Mahmood  1 , Santosh K Mandal  1 , Khaggeswar Bheemanapally  1 , Mostafa M H Ibrahim  1 , K P Briski  2
Affiliations

Norepinephrine control of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter expression in the female rat: Role of monocarboxylate transporter function

A S M Hasan Mahmood et al. Mol Cell Neurosci. 2019 Mar.

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.

Keywords: Glutamate decarboxylase; Glycogen phosphorylase; Monocarboxylate transporter; Nitric oxide synthase; Norepinephrine; Ventromedial hypothalamic nucleus.

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Conflict of interest statement

Competing Interests Statement:

The authors have no competing interests to declare.

Figures

Figure 1.
Figure 1.. Effects of the Monocarboxylate Transporter Inhibitor Alpha-Cyano-4-Hydroxycinnamic Acid (4CIN) on Norepinephrine (NE) Regulation of Ventromedial Hypothalamic Nucleus (VMN) Glycogen Synthase (GS) and Glycogen Phosphorylase (GP) Protein Expression in the Female Rat.
Groups of estradiol-implanted ovariectomized female rats (n=6/treatment group) were bilaterally injected into the VMN with NE after pretreatment delivery of vehicle (NE/V; solid gray bars) or 4CIN (NE/4CIN; diagonal-striped gray bars) into that structure. Controls were given vehicle only (V/V; white bars) into the VMN. For each treatment group, three separate aliquot pools of micropunched VMN tissue were analyzed by Western blot for GS or GP. Bars depict mean normalized protein optical density (O.D.) measures ± S.E.M. *p<0.05; **p<0.01.
Figure 2.
Figure 2.. Effects of 4CIN Pretreatment on NE-Associated Patterns of Glutamate Decarboxylase65/67 (GAD65/67), Neuronal Nitric Oxide Synthase (nNOS), and Steroidogenic Factor-1 (SF-1) Protein Expressin in Female Rats.
Bars depict mean normalized GAD (Panel A), nNOS (Panel B), or SF-1 (Panel C) protein O.D. measures ± S.E.M. for V/V (white bars), NE/V (solid gray bars), and NE/4CIN (diagonal-striped gray bars) treatment groups. *p<0.05; **p<0.01; ***p<0.001.
Figure 3.
Figure 3.. VMN Astrocyte Adrenoreceptor Protein Expression in NE-Treated Female Rats.
Astrocytes were immunolabeled for the marker protein glial fibrillary acidic protein (GFAP) prior to laser-catapult microdssection from 10 μm-thick fresh frozen sections cut through the VMN. Alpha1 adrenergic (α1AR; Panel A), alpha2 adrenergic (α2AR; Panel B), and beta1 adrenergic (β1AR; Panel C) receptor proteins were each analyzed by Western blot in triplicate pools of n=60 astrocyte lysates (n=10 cells per subject) for each treatment group. Data depict mean normalized protein O.D. values ± S.E.M. for V/V (white bars), NE/V (solid gray bars), and NE4CIN (diagonal-striped gray bars) treatment groups. *p<0.05; ***p<0.001.
Figure 4.
Figure 4.. NE Regulation of VMN Astrocyte Estrogen Receptor Protein Expression in Cc- Versus Vehicle-Pretreated Rats.
GFAP-immunopositive astrocyte lysates pools (n=60 cells per pool) were analyzed in triplicate, for each treatment group, for estrogen receptor-alpha (ERα; Panel A), estrogen receptor-beta (ERβ; Panel B), or GRP30 (Panel C). Data depict mean normalized protein O.D. values ± S.E.M. for V/V (white bars), NE/V (solid gray bars), and NE/4CIN (diagonal-striped gray bars) treatment groups. *p<0.05; **p<0.01.
Figure 5.
Figure 5.. Effects of 4CIN Pretreatment on Glucose, Glucagon, Corticosterone, and Free Fatty Acid Responses to Intra-VMN NE Administration.
Data depict mean glucose (Panel A), free fatty acid (Panel B), plasma glucagon (Panel C), and corticosterone (Panel D) levels ± S.E.M. for V/V (white bars), NE/V (solid gray bars), and NE/4CIN (diagonal-striped gray bars) treatment groups. *p<0.05; **p<0.01; ***p<0.001.
Figure 6.
Figure 6.. Model for monocarboxylate transport-dependent regulation of VMN gluco-regulatory neurotransmission by norepinephrine.
Hindbrain catecholaminergic neurons [Panel A] are a source of regulatory input to the female VMN that controls GP protein responses to hypoglycemia [Tamrakar et al., 2015]. Current data show that VMN astrocytes (depicted in gold) express the adrenergic receptor subtypes α1AR, α2AR, and β1AR [depicted in blue; enlarged rectangle, Panel A], and that NE to the VMN alters expression levels of these receptors as well as the glycolytic enzymes glycogen synthase and phosphorylase [bottom, Panel B]. NE suppresses expression of nNOS, a protein marker of counter-regulation – stimulatory NO neurons (light gray), and enhances GAD65/67 levels, indicative of elevated release of the counter-regulation inhibitor GABA (dark gray); these transmitter responses are indicated by blue asterisks in Panel B. Purple asterisks denote that pretreatment with the monocarboxyate transporter inhibitor 4CIN normalizes patterns of nNOS and GAD expression. Current results imply that noradrenergic regulation of female VMN glucoregulatory neurotransmission involves, in part, control of monocarboxylate substrate fuel supply associated with glycogen breakdown.
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