Effects of acute versus recurrent insulin-induced hypoglycemia on ventromedial hypothalamic nucleus metabolic-sensory neuron AMPK activity: Impact of alpha1-adrenergic receptor signaling

Briski, Karen P.; Mandal, Santosh K.; Bheemanapally, Khaggeswar; Ibrahim, Mostafa M.H.

doi:10.1016/j.brainresbull.2020.01.013

Cited by 21 publications

(21 citation statements)

References 29 publications

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“…The neurotransmitters GABA and NO act within VMN neural circuities to correspondingly suppress or amplify counter-regulatory hormone secretion during hypoglycemia [27] , [28] . Western blot analysis of pooled lysates of nitrergic and GABAergic neurons collected at regular intervals over the rostro-caudal extent of the male VMN revealed elevated pAMPK/AMPK protein ratios in each nerve cell population at a post-insulin injection time point similar to that used here [8] , [9] . Present outcomes point to a need for a functional mapping approach to establish the neuroanatomical distribution of GABA and NO neurons within the VMN that exhibit neuroestradiol-dependent adjustments in neurotransmission during hypoglycemia, and to determine if hypoglycemia-sensitive cells of each transmitter type express aromatase and/or AMPK.…”

Section: Discussionmentioning

confidence: 65%

“…Activation of mediobasal hypothalamic (MBH) AMPK is obligatory for optimum glucose counter-regulatory responses to insulin-induced hypoglycemia [6] , [7] . The ventromedial hypothalamic nucleus (VMN), a prominent neuroanatomical component of the MBH, is a likely source of AMPK gluco-regulatory signaling as hypoglycemia increases AMPK phosphorylation in VMN neurons that express characterized gluco-inhibitory (γ-aminobutyric acid; GABA) or stimulatory (nitric oxide; NO) neurotransmitters [8] , [9] .…”

Section: Introductionmentioning

confidence: 99%

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Neuroestradiol regulation of ventromedial hypothalamic nucleus 5′-AMP-activated protein kinase activity and counterregulatory hormone secretion in hypoglycemic male versus female rats

Uddin

Briski

2021

AIMS Neuroscience

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Neuroestradiol regulation of ventromedial hypothalamic nucleus 5′-AMP-activated protein kinase activity and counterregulatory hormone secretion in hypoglycemic male versus female rats

Uddin

Briski

2021

AIMS Neuroscience

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“…Mediobasal hypothalamic (MBH) AMPK activation is obligatory for optimum counter-regulatory reactivity to IIH ( Han et al, 2005 ; McCrimmon et al, 2008 ). The VMN is a crucial site for integration of nutrient, endocrine, and neurochemical indicators of metabolic state that shape glucose counter-regulation; within the MBH, it is a plausible source of AMPK gluco-regulatory signaling as hypoglycemia increases AMPK phosphorylation in VMN GABAergic and nitrergic neurons ( Briski et al, 2020 ; Ibrabim et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Glycogen Phosphorylase Isoform Regulation of Ventromedial Hypothalamic Nucleus Gluco-Regulatory Neuron 5′-AMP-Activated Protein Kinase and Transmitter Marker Protein Expression

2021

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Brain glycogen is remodeled during metabolic homeostasis and provides oxidizable L-lactate equivalents. Brain glycogen phosphorylase (GP)-brain (GPbb; AMP-sensitive) and -muscle (GPmm; norepinephrine-sensitive) type isoforms facilitate stimulus-specific control of glycogen disassembly. Here, a whole animal model involving stereotactic-targeted delivery of GPmm or GPbb siRNA to the ventromedial hypothalamic nucleus (VMN) was used to investigate the premise that these variants impose differential control of gluco-regulatory transmission. Intra-VMN GPmm or GPbb siRNA administration inhibited glutamate decarboxylate65/67 (GAD), a protein marker for the gluco-inhibitory transmitter γ--aminobutyric acid (GABA), in the caudal VMN. GPbb knockdown, respectively overturned or exacerbated hypoglycemia-associated GAD suppression in rostral and caudal VMN. GPmm siRNA caused a segment-specific reversal of hypoglycemic augmentation of the gluco-stimulatory transmitter indicator, neuronal nitric oxide synthase (nNOS). In both cell types, GP siRNA down-regulated 5′-AMP-activated protein kinase (AMPK) during euglycemia, but hypoglycemic suppression of AMPK was reversed by GPmm targeting. GP knockdown elevated baseline GABA neuron phosphoAMPK (pAMKP) content, and amplified hypoglycemic augmentation of pAMPK expression in each neuron type. GPbb knockdown increased corticosterone secretion in eu- and hypoglycemic rats. Outcomes validate efficacy of GP siRNA delivery for manipulation of glycogen breakdown in discrete brain structures in vivo, and document VMN GPbb control of local GPmm expression. Results document GPmm and/or -bb regulation of GABAergic and nitrergic transmission in discrete rostro-caudal VMN segments. Contrary effects of glycogenolysis on metabolic-sensory AMPK protein during eu- versus hypoglycemia may reflect energy state-specific astrocyte signaling. Amplifying effects of GPbb knockdown on hypoglycemic stimulation of pAMPK infer that glycogen mobilization by GPbb limits neuronal energy instability during hypoglycemia.

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“…Neurochemicals that mediate effects of ventromedial hypothalamic energy imbalance include the amino acid γ-aminobutyric acid (GABA), which suppresses glucagon and epinephrine responses to hypoglycemia 6 , and the gaseous transmitter nitric oxide (NO), which is stimulatory to counter-regulatory hormone release 7 . VMN GABAergic and nitrergic neurons are an evident direct source of information on cellular energy stability as both nerve cell types source express the ultra-sensitive energy gauge 5′-AMP-activated protein kinase (AMPK) 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

UHPLC–electrospray ionization–mass spectrometric analysis of brain cell-specific glucogenic and neurotransmitter amino acid content

Bheemanapally

Napit

Ibrahim

et al. 2021

Sci Rep

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Astrocyte glycogen, the primary energy reserve in brain, undergoes continuous remodeling by glucose passage through the glycogen shunt prior to conversion to the oxidizable energy fuel l-lactate. Glucogenic amino acids (GAAs) are a potential non-glucose energy source during neuro-metabolic instability. Current research investigated whether diminished glycogen metabolism affects GAA homeostasis in astrocyte and/or nerve cell compartments. The glycogen phosphorylase (GP) inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) was injected into the ventromedial hypothalamic nucleus (VMN), a key metabolic-sensing structure, before vehicle or l-lactate infusion. Pure VMN astrocyte and metabolic-sensory neuron samples were obtained by combinatory immunocytochemistry/laser–catapult-microdissection for UHPLC–electrospray ionization–mass spectrometry (LC–ESI–MS) GAA analysis. DAB inhibition of VMN astrocyte aspartate and glutamine (Gln) levels was prevented or exacerbated, respectively, by lactate. VMN gluco-stimulatory nitric oxide (NO; neuronal nitric oxide synthase-immunoreactive (ir)-positive) and gluco-inhibitory γ-aminobutyric acid (GABA; glutamate decarboxylase65/67-ir-positive) neurons exhibited lactate-reversible asparate and glutamate augmentation by DAB, but dissimilar Gln responses to DAB. GP inhibition elevated NO and GABA nerve cell GABA content, but diminished astrocyte GABA; these responses were averted by lactate in neuron, but not astrocyte samples. Outcomes provide proof-of-principle of requisite LC–ESI–MS sensitivity for GAA measurement in specific brain cell populations. Results document divergent effects of decreased VMN glycogen breakdown on astrocyte versus neuron GAAs excepting Gln. Lactate-reversible DAB up-regulation of metabolic-sensory neuron GABA signaling may reflect compensatory nerve cell energy stabilization upon decline in astrocyte-derived metabolic fuel.

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Effects of acute versus recurrent insulin-induced hypoglycemia on ventromedial hypothalamic nucleus metabolic-sensory neuron AMPK activity: Impact of alpha1-adrenergic receptor signaling

Cited by 21 publications

References 29 publications

Neuroestradiol regulation of ventromedial hypothalamic nucleus 5′-AMP-activated protein kinase activity and counterregulatory hormone secretion in hypoglycemic male versus female rats

Neuroestradiol regulation of ventromedial hypothalamic nucleus 5′-AMP-activated protein kinase activity and counterregulatory hormone secretion in hypoglycemic male versus female rats

Glycogen Phosphorylase Isoform Regulation of Ventromedial Hypothalamic Nucleus Gluco-Regulatory Neuron 5′-AMP-Activated Protein Kinase and Transmitter Marker Protein Expression

UHPLC–electrospray ionization–mass spectrometric analysis of brain cell-specific glucogenic and neurotransmitter amino acid content

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