Hindbrain medulla catecholamine cell group involvement in lactate-sensitive hypoglycemia-associated patterns of hypothalamic norepinephrine and epinephrine activity

Shrestha, Pooja; Tamrakar, Pratistha; Ibrahim, Baher A.; Briski, Karen P.

doi:10.1016/j.neuroscience.2014.07.033

Cited by 26 publications

(31 citation statements)

References 28 publications

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“…Precedent exposure to serial bouts of hypoglycemia caused opposite changes in basal A2 neuron DβH protein expression in estradiol-vs. oil-implanted OVX female rats, plus exacerbation of these divergent adjustments by renewed hypoglycemia. As these cells communicates hypoglycemia-associated cell energy imbalance signaling (Gujar et al 2014;Shrestha et al 2014), estradiol-dependent adaptive down-regulation of noradrenergic neurotransmission by A2 neurons implies that this hormone may promote a positive energy state during this recurring metabolic stress. Estradiol also regulates effects of recurrent hypoglycemia on enzyme proteins involved in energy metabolism and fatty acid synthesis.…”

Section: Discussionmentioning

confidence: 99%

Impact of recurrent hypoglycemic stress on hindbrain A2 nerve cell energy metabolism and catecholamine biosynthesis: modulation by estradiol

Tamrakar¹,

Briski²

2017

Acta Neurobiologiae Experimentalis

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It is unclear if habituation of hindbrain A2 metabolo-sensory neurons to recurrent insulin-induced hypoglycemia (RIIH) correlates with estradiol-dependent adjustments in energy metabolism that favor positive energy balance. Laser-microdissected A2 cells from estradiolor oil-implanted ovariectomized female rats were analyzed by Western blot to assess effects of three prior daily insulin injections on basal and hypoglycemic patterns of catecholamine biosynthetic enzyme dopamine-beta-hydroxylase (DβH) and rate-limiting energy pathway enzyme protein expression. Precedent hypoglycemia respectively decreased or increased baseline DβH expression in estradiol-(E) vs. oil (O)-treated rats; this protein profile was further suppressed or augmented in those animals at 2 hr after re-induction of hypoglycemia. These data suggest that estradiol may curtail A2 noradrenergic-controlled functions both in the midst of and between hypoglycemic bouts. Results also show that prior hypoglycemia exposure upregulated A2 neuron glycolytic enzyme protein levels when E was present, and exerted differential effects on basal and hypoglycemia-associated respiratory chain and fatty acid synthetic pathway enzyme expression. E may thus accordingly amplify glycolysis-derived metabolites/energy, coupled with reduced reliance on oxidative phosphorylation, and activate the fatty acid synthetic pathway during RIIH. E may also be of benefit by preventing maladaptive reductions in A2 neuron Krebs cycle/electron transport enzyme expression during re-exposure to hypoglycemia. Augmentation of negative energy balance during this recurring metabolic stress in the absence of E is a likely impetus for augmented vs. decreased A2 signaling of energy imbalance by DβH in O vs. E rats during RIIH.

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Section: Discussionmentioning

confidence: 99%

Impact of recurrent hypoglycemic stress on hindbrain A2 nerve cell energy metabolism and catecholamine biosynthesis: modulation by estradiol

Tamrakar¹,

Briski²

2017

Acta Neurobiologiae Experimentalis

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“…Individual forebrains were cut into serial 100 μm frozen sections through the preoptic area and hypothalamus. The Palkovits micropunch technique was used to dissect the anteroventral periventricular nucleus [AVPV; −0.00 to −0.26 mm]; medial preoptic nucleus [MPN; −0.26 to −0.60 mm]; paraventricular hypothalamic nucleus [PVH; −1.78 to −2.00 mm]; arcuate hypothalamic nucleus [ARH; −1.78 to −3.25 mm]; ventromedial hypothalamic nucleus [VMH; −2.00 to −3.25 mm]; dorsomedial hypothalamic nucleus [DMH; −2.45 to −3.25 mm]; and lateral hypothalamic area [LHA; −1.78 to 3.28 mm] over pre-determined rostro-caudal intervals relative to bregma [Shrestha et al, 2014]. Tissue samples were obtained using calibrated Palkovits-style hollow punch tools of 0.29 mm- [AVPV], 0.51 mm- [MPN, PVH, ARH, VMH and DMH], or 0.76 mm- [LHA] diameter [prod.…”

Section: Methodsmentioning

confidence: 99%

“…no. BA E-5200; Rocky Mountain Diagnostics, Inc., Colorado Springs, CO), per kit instructions [Shrestha et al, 2014]. Briefly, standard (10 uL) and control (10 uL) solutions and sample aliquots (80 uL) were pipetted into individual extraction plate wells, then diluted to 100 uL with distilled water.…”

Section: Methodsmentioning

confidence: 99%

“…Individual hypothalamic metabolic loci were microdissected by the Palkovits punch method after drug delivery for measurements of total/phosphorylated AMPK and neuropeptide transmitter levels. Recent findings point to A2 neurons as a principal source of noradrenergic signaling of hypoglycemia-associated adjustments in substrate fuel status from the hindbrain to multiple hypothalamic metabolic loci in male rats [Shrestha et al, 2014]. Here, we examined whether inhibition of caudal DVC AMPK activity alters tissue norepinephrine (NE) levels in those sites, and if estradiol controls the magnitude and/or direction of changes in NE activity in a site-specific manner.…”

Section: Introductionmentioning

confidence: 99%

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Role of estradiol in intrinsic hindbrain AMPK regulation of hypothalamic AMPK, metabolic neuropeptide, and norepinephrine activity and food intake in the female rat

et al. 2016

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This study addressed the hypothesis that dorsomedial hindbrain adenosine 5’-monophosphate-activated protein kinase (AMPK) imposes inherent control over hypothalamic AMPK, neuropeptide, and norepinephrine (NE) activity and governs feeding in an estradiol-dependent manner. Groups of estradiol (E)- or oil (O)-implanted ovariectomized rats were injected with the AMPK inhibitor Compound C (Cc) or vehicle into the caudal fourth ventricle (CV4) prior to micropunch-dissection of individual hypothalamic metabolic loci or assessment of food intake. Cc decreased hindbrain dorsal vagal complex phosphoAMPK (pAMPK) profiles in both E and O; tissue ATP levels were reduced by this treatment in O only. In E/Cc, pAMPK expression was diminished in the lateral hypothalamic area (LHA) and ventromedial (VMH) and paraventricular (PVH) nuclei; only PVH pAMPK was suppressed by this treatment in O/Cc. Cc decreased PVH corticotropin-releasing hormone and arcuate (ARH) proopiomelanocortin (POMC) and neuropeptide Y in O, but suppressed only POMC in E. O/Cc exhibited both augmented (PVH, VMH) and decreased (LHA, ARH) hypothalamic NE content, whereas Cc treatment of E elevated preoptic and dorsomedial hypothalamic nucleus NE. Cc completely or incompletely repressed feeding in E versus O, respectively. Results implicate dorsomedial hindbrain AMPK in physiological stimulus-induced feeding in females. Excepting POMC, hypothalamic neuropeptide targets of input from that sensor may differ in presence vs. absence of estrogen. Estradiol likely determines hypothalamic targets of altered NE signaling due to hindbrain AMPK activation. Divergent changes in NE content of hypothalamic loci in O/Cc uniquely demonstrate sensor-induced bimodal catecholamine signaling to those sites.

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“…For each rat, tissue punches of each dissected structure were collected in 100 μL of 0.01 N HCl containing 1 mM EDTA and 4 mM sodium metabisulfite; in each treatment group, aliquots from subjects were pooled to create triplicate samples for ELISA analysis of NE content [Shrestha et al, 2014]. For both the AVPV and ARH, aliquots of tissue lysate were combined within treatment groups to create four sample pools for Western blot analysis of prepro-kisspeptin protein levels, using a goat polyclonal antiserum (sc-18134; Santa Cruz Biotechnol.).…”

Section: Methodsmentioning

confidence: 99%

Hindbrain estrogen receptor-beta antagonism normalizes reproductive and counter-regulatory hormone secretion in hypoglycemic steroid-primed ovariectomized female rats

Briski

Shrestha

2016

Neuroscience

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Hindbrain dorsal vagal complex A2 noradrenergic signaling represses the pre-ovulatory luteinizing hormone (LH) surge in response to energy deficiency. Insulin-induced hypoglycemia augments A2 neuron adenosine 5′-monophosphate-activated protein kinase (AMPK) activity and estrogen receptor-beta (ERβ) expression, coincident with LH surge suppression. We hypothesized that ERβ is critical for hypoglycemia-associated patterns of LH secretion and norepinephrine (NE) activity in key reproduction-relevant forebrain structures. The neural mechanisms responsible for tight coupling of systemic energy balance and procreation remain unclear; here, we investigated whether ERβ-dependent hindbrain signals also control glucose counter-regulatory responses to hypoglycemia. Gonadal steroid-primed ovariectomized female rats were pretreated by caudal fourth ventricular administration of the ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) or vehicle at LH surge onset before insulin injection. Western blot analysis of laser-microdissected A2 neurons revealed hypoglycemic augmentation of 5′-monophosphate-activated protein kinase activity and dopamine-β-hydroxylase protein expression; the latter response was attenuated by PHTPP pretreatment. PHTPP regularized LH release, but not preoptic GnRH-I precursor protein expression in insulin-injected rats, and reversed hypoglycemic stimulation of glucagon and corticosterone secretion. Hypoglycemia caused PHTPP-reversible changes in NE and prepro-kisspeptin protein content in the hypothalamic arcuate (ARH), but not anteroventral periventricular nucleus. Results provide novel evidence for ERβ-dependent caudal hindbrain regulation of LH and counter-regulatory hormone secretion during hypoglycemia. That inhibition of LH likely involves mechanisms at the axon terminal that impede GnRH neurotransmission. Data also show that caudal hindbrain ERβ exerts site-specific control of NE activity in forebrain projection sites during hypoglycemia, including the ARH where prepro-kisspeptin may be a target of this signaling.

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Hindbrain medulla catecholamine cell group involvement in lactate-sensitive hypoglycemia-associated patterns of hypothalamic norepinephrine and epinephrine activity

Cited by 26 publications

References 28 publications

Impact of recurrent hypoglycemic stress on hindbrain A2 nerve cell energy metabolism and catecholamine biosynthesis: modulation by estradiol

Impact of recurrent hypoglycemic stress on hindbrain A2 nerve cell energy metabolism and catecholamine biosynthesis: modulation by estradiol

Role of estradiol in intrinsic hindbrain AMPK regulation of hypothalamic AMPK, metabolic neuropeptide, and norepinephrine activity and food intake in the female rat

Hindbrain estrogen receptor-beta antagonism normalizes reproductive and counter-regulatory hormone secretion in hypoglycemic steroid-primed ovariectomized female rats

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