Role of hindbrain adenosine 5′-monophosphate-activated protein kinase (AMPK) in hypothalamic AMPK and metabolic neuropeptide adaptation to recurring insulin-induced hypoglycemia in the male rat

Mandal, Santosh K.; Shrestha, Pooja; Alenazi, Fahaad; Shakya, Manita; Alhamami, Hussain N.; Briski, Karen P.

doi:10.1016/j.npep.2017.08.001

Cited by 17 publications

(8 citation statements)

References 55 publications

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“…Each forebrain was cut into alternating series of 100 μm-or 10 μm-thick frozen sections over the length of the VMN, over repeating distances of 200 μm (2 × 100 μm sections) and 100 μm (10 × 10 μm thick sections), respectively. VMN tissue was micropunch-dissected from 100 μm sections using 0.50 mm-diameter hollow kneedles (Stoelting, Inc., and collected into lysis buffer [2.0% sodium dodecyl sulfate (SDS), 0.05 M dithiothreitol, 10.0% glycerol, 1.0 mM EDTA, 60 mM Tris-HCl, pH 7.2] for heat denaturation, as described [Mandal et al, 2017;Alhamami et al, 2018]. For each protein of interest, three separate tissue aliquot pools were created for each treatment group ahead of separation in BioRad TGX 10-12% stain-free gels (prod.…”

Section: Western Blot Analysis Of Micropunch-dissected Vmn Tissuementioning

confidence: 99%

“…Blood glucose levels were determined using an ACCU-CHECK Aviva plus glucometer (Roche Diagnostic Corporation, Indianapolis, IN) [Kale et al, 2006]. Plasma free fatty acid (FFA) concentrations were measured with Free Fatty Acid Quantitation Kit reagents (MAK044; Sigma Aldrich, St. Louis, Mo) [Briski et al, 2017]. Plasma corticosterone (ADI-900-097; Enzo Life Sciences, Inc., Farmingdale, NY) and glucagon (EZGLU-30K, EMD Millipore, Billerica, MA) concentrations were determined using commercial ELISA kit reagents, as described [Alhamani et al, 2018].…”

Section: Glucose and Counter-regulatory Hormone Measurementsmentioning

confidence: 99%

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

Mahmood

Mandal

Bheemanapally

et al. 2019

Molecular and Cellular Neuroscience

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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. The 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 alphacyano-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 decarboxylase 65/67) 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 downregulated adrenoreceptor (AR), e.g. alpha 1 and alpha 2 , alongside amplified beta 1 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.

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Section: Western Blot Analysis Of Micropunch-dissected Vmn Tissuementioning

confidence: 99%

Section: Glucose and Counter-regulatory Hormone Measurementsmentioning

confidence: 99%

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

Mahmood

Mandal

Bheemanapally

et al. 2019

Molecular and Cellular Neuroscience

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“…Each forebrain was cut into alternating series of 100-µm- or 10-µm-thick frozen sections over the length of the VMN, over repeating distances of 200 µm (2 × 100 µm sections) and 100 µm (10 × 10-µm-thick sections), respectively. VMN tissue was micropunch-dissected from 100-µm sections using 0.50-mm diameter hollow kneedles (Stoelting, Inc., Wood Dale, IL) and collected into lysis buffer (2.0% sodium dodecyl sulfate [SDS], 0.05 M dithiothreitol, 10.0% glycerol, 1.0 mM EDTA, 60 mM Tris-HCl, pH 7.2) for heat denaturation, as described (Mandal et al., 2017; Alhamami et al., 2018). For each protein of interest, three separate tissue aliquot pools were created for each treatment group prior to separation in BioRad TGX 10% stain-free gels (prod.…”

Section: Methodsmentioning

confidence: 99%

Estrogen Receptor Involvement in Noradrenergic Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neurotransmitter and Stimulus-Specific Glycogen Phosphorylase Enzyme Isoform Expression

et al. 2020

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Norepinephrine (NE) directly regulates ventromedial hypothalamic nucleus (VMN) glucoregulatory neurons and also controls glycogen-derived fuel provision to those cells. VMN nitric oxide (NO) and c-aminobutyric acid (GABA) neurons and astrocytes express estrogen receptor-alpha (ERa) and ER-beta (ERb) proteins. Current research used selective ERa (1,3Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride) or ERb (4-[2-phenyl-5,7bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol) antagonists to address the premise that these ERs govern basal and/or NE-associated patterns of VMN metabolic neuron signaling and astrocyte glycogen metabolism. Both ERs stimulate expression of the enzyme marker protein neuronal nitric oxide synthase, not glutamate decarboxylase 65/67. NE inhibition or augmentation of neuronal nitric oxide synthase and glutamate decarboxylase 65/67 profiles was ER-independent or-dependent, respectively. In both neuron types, VMN ERb activity inhibited baseline alpha1-(a 1-) and/or alpha2-(a 2-)adrenergic receptor (AR) expression, but ERa and-b signaling was paradoxically crucial for noradrenergic upregulation of a 2-AR. NE inhibited glycogen synthase expression and exerted opposite effects on VMN adenosine monophosphate-sensitive glycogen phosphorylase (GP)-brain type (stimulatory) versus NE-sensitive GP muscle (inhibitory) via ERa orb activity. Results document unique ERa and ERb actions on metabolic transmitter and AR protein expression in VMN nitrergic versus GABAergic neurons. ER effects varied in the presence versus absence of NE, indicating that both neuron types are substrates for estradiol and noradrenergic regulatory interaction. NE-dependent ER control of VMN GP variant expression implies that these signals also act on astrocytes to direct physiological stimulus-specific control of glycogen metabolism, which may in turn influence GABA transmission.

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“…Regional micro-dissection of VMNvl tissue was performed here as recent studies show that INS-induced hypoglycemia effects on whole-VMN glycogen content vary along the longitudinal axis of the VMN (Ibrahim et al, 2020b). Accuracy of use of micropunch methodology for collection of distinctive hypothalamic loci of interest, including the VMN, as indicated by marker protein expression, has been validated (Mandal et al, 2017;. In each treatment group, tissue lysate aliquots from individual subjects were pooled from rostral middle, or caudal VMNvl segments to create for each target protein, at minimum, triplicate sample pools per level.…”

Section: Vmn Tissue Micropunch Dissection and Western Blot Analysismentioning

confidence: 99%

Hypoglycemic and post-hypoglycemic patterns of glycogen phosphorylase isoform expression in the ventrolateral ventromedial hypothalamic nucleus: impact of sex and estradiol

Bheemanapally

Alhamyani

Alshamrani

et al. 2021

Acta Neurobiologiae Experimentalis

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Glycogen metabolism shapes ventromedial hypothalamic nucleus (VMN) control of glucose homeostasis. Brain glycogen mass undergoes compensatory expansion post-recovery from insulin-induced hypoglycemia (IIH). Current research utilized combinatory high-resolution microdissection/high-sensitivity Western blotting to investigate whether IIH causes residual adjustments in glycogen metabolism within the metabolic-sensory ventrolateral VMN (VMNvl). Micropunch-dissected tissue was collected from rostral, middle, and caudal levels of the VMNvl in each sex for analysis of glycogen synthase (GS) and glycogen phosphorylase (GP)-muscle type (GPmm; norepinephrine-sensitive) and GP-brain type (GPbb; glucoprivic-sensitive) isoform expression during and after IIH. Hypoglycemic suppression of VMNvl GS levels in males disappeared or continued after reestablishment of euglycemia, according to sampled segment. Yet, reductions in female VMNvl GS persisted after IIH. Males exhibited reductions in GPmm content in select rostro-caudal VMNvl segments, but this protein declined in each segment post-hypoglycemia. Females, rather, showed augmented or diminished GPmm levels during IIH, but no residual effects of IIH on this protein. In each sex, region-specific up-or down-regulation of VMNvl GPbb profiles during glucose decrements were undetected post-recovery from IIH. Results provide novel proof of estradiol-dependent sex-dimorphic patterns of VMNvl GP variant expression at specific rostro-caudal levels of this critical gluco-regulatory structure. Sex differences in persistence of IIH-associated GS and GPmm patterns of expression after restoration of euglycemia infer that VMNvl recovery from this metabolic stress may involve dissimilar glycogen accumulation in male versus female.

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Role of hindbrain adenosine 5′-monophosphate-activated protein kinase (AMPK) in hypothalamic AMPK and metabolic neuropeptide adaptation to recurring insulin-induced hypoglycemia in the male rat

Cited by 17 publications

References 55 publications

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

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

Estrogen Receptor Involvement in Noradrenergic Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neurotransmitter and Stimulus-Specific Glycogen Phosphorylase Enzyme Isoform Expression

Hypoglycemic and post-hypoglycemic patterns of glycogen phosphorylase isoform expression in the ventrolateral ventromedial hypothalamic nucleus: impact of sex and estradiol

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