Lateral but not Medial Hypothalamic AMPK Activation Occurs at the Hypoglycemic Nadir in Insulin-injected Male Rats: Impact of Caudal Dorsomedial Hindbrain Catecholamine Signaling

Alhamami, Hussain N.; Uddin, Md. Main; Mahmood, Akhtar; Briski, Karen P.

doi:10.1016/j.neuroscience.2018.03.001

Cited by 15 publications

(19 citation statements)

References 46 publications

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“…INS-injected female rats exhibited ERβ-dependent augmentation of VMN SF-1 profiles and ER-independent amplification of BDNF expression, whereas both transmitters profiles were refractory to IIH in males. Indeed, we previously reported that SF-1 expression does not differ between eu-and hypoglycemia male rats [Alhamami et al, 2018b]. It remains unclear if SF-1 neurons in the female VMN express ERβ, or respond to ERβ regulation of upstream neurons.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in forebrain estrogen receptor regulation of hypoglycemic patterns of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and astrocyte glycogen metabolic enzyme expression

et al. 2018

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

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Section: Discussionmentioning

confidence: 99%

Sex differences in forebrain estrogen receptor regulation of hypoglycemic patterns of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and astrocyte glycogen metabolic enzyme expression

et al. 2018

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“…After surgery, rats were injected subcutaneously (sc) with ketoprofen (1 mg/kg bw) and intramuscularly with enrofloxacin (10 mg/0.1 mL), treated by topical application of 0.25% bupivacaine to closed incisions, then transferred to individual cages. At 9:00 h on days 7 and 9, groups 1 (n=4) and 3 (n=4) were injected into the CV4 with vehicle (v), e.g., sterile apyrogenic water containing 0.2% ascorbic acid, while groups 2 (n=4) and 4 (n=4) rats received 6-hydroxydopamine (6OHDA; 75 ug/1.0 µL (Gujar et al, 2014;Tamrakar et al, 2015;Alhamami et al, 2018). Beginning at 9:00 h on day 10, animals in groups 1 and 2 were infused into CV4 with vehicle (60% DMSO : 40% 0.9% NaCl; 2.0 µL), over a 30 min period using a 33-gauge internal injection cannula (prod.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

“…Micropunch-dissected VMN tissue was analyzed by Western blotting and ELISA methods to determine 4CIN effects on VMN GAD 65/67 protein expression and NE activity, respectively. A subset of subjects in each treatment group were pretreated by intra-CV4 delivery of the selective catecholamine neurotoxin 6-hydroxydopamine (6OHDA) (Gujar et al, 2013;Tamrakar et al, 2015;Alhamami et al, 2018) to verify the role of DVC NE in hindbrain lactoprivic regulation of VMN GAD 65/67 .…”

Section: Introductionmentioning

confidence: 99%

Hindbrain metabolic deficiency regulates ventromedial hypothalamic nucleus glycogen metabolism and glucose-regulatory signaling

Briski¹,

Mandal²

2020

Acta Neurobiologiae Experimentalis

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The catecholamine norepinephrine (NE) links hindbrain metabolic-sensory neurons with downstream gluco-regulatory loci, including the ventromedial hypothalamic nucleus (VMN). Exogenous NE up-regulates VMN expression of glutamate decarboxylase (GAD), biomarker for the gluco-inhibitory transmitter γ-aminobutryic acid (GABA). Brain glycogen phosphorylase (GP)-muscle (GPmm) and -brain (GPbb) variants are stimulated in vitro by NE or energy deficiency, respectively. Current research investigated whether lactoprivic-driven VMN NE signaling regulates GABA and if VMN GPmm and GPbb profiles react differently to that deficit cue. Male rats were pretreated by caudal fourth ventricle delivery of the selective catecholamine neurotoxin 6-hydroxydopamine (6OHDA) ahead of the monocarboxylate transporter inhibitor alpha-cyano-4-hydroxycinnamic acid (4CIN). Micropunch-dissected VMN tissue was analyzed by Western blot and ELISA to assess NE-dependent 4CIN regulation of GAD and GP variant protein expression and NE activity. 4CIN caused 6OHDA-reversible augmentation of VMN NE content and plasma glucose and counter-regulatory hormone levels. 6OHDA stimulated basal VMN GAD expression, but prevented 4CIN stimulation of this profile. Neurotoxin inhibited or increased baseline VMN GPmm and GPbb levels, respectively, in non-4CIN-injected rats. 6OHDA deterred 4CIN inhibition of GPmm, but did not prevent drug stimulation of GPbb. Results affirm hindbrain lactoprivic regulation of glucostasis. Hindbrain NE exerts opposite effects on VMN GABA transmission during hindbrain lactostasis vs. -privation. VMN norepinephrine-vs. energy-sensitive GP variants are subject to dissimilar NE regulation during energy homeostasis, and respond differently to hindbrain lactoprivation.

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“…Glycogen metabolism is controlled by opposing glycogen synthase (GS) and glycogen phosphorylase (GP) enzyme actions that catalyze glycogen synthesis or breakdown, respectively. Our findings that pharmacological suppression of VMN GP activity by 1,4-dideoxy-1,4-imino-d-arabinitol up-regulates the VMN nNOS expression in each sex (Alshamrani and Briski, personal communication) [40], and inhibits GAD profiles in females Noradrenergic regulation of VMN astrocyte glycogen metabolism. Brain astrocytes store glycogen as a vital metabolic fuel reserve; this depot exhibits a dynamic turnover during normal brain activity and metabolic homeostasis, and is a critical source of lactate equivalents during heightened neural activity or brain glucose deficiency [37].…”

mentioning

confidence: 60%

“…Glycogen metabolism is controlled by opposing glycogen synthase (GS) and glycogen phosphorylase (GP) enzyme actions that catalyze glycogen synthesis or breakdown, respectively. Our findings that pharmacological suppression of VMN GP activity by 1,4-dideoxy-1,4-imino-d-arabinitol up-regulates the VMN nNOS expression in each sex (Alshamrani and Briski, personal communication) [40], and inhibits GAD profiles in females (Alshamrani and Briski, personal communication), imply that astrocyte glycogen-derived energy fuel streams affect neuro-metabolic stability in that structure, and that diminished astrocyte glycogen mass or turnover may be interpreted by VMN gluco-regulatory neurons as indicative of energy deficiency. NE has well documented regulatory effects on astrocyte glycogen metabolism in vitro [41,42].…”

mentioning

confidence: 87%

Norepinephrine Regulation of Ventromedial Hypothalamic Nucleus Metabolic-Sensory Neuron 5′-AMP-Activated Protein Kinase Activity: Impact of Estradiol

Mahmood

Uddin

Ibrahim

et al. 2020

IJMS

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The mediobasal hypothalamus (MBH) shapes the neural regulation of glucostasis by 5′-AMP-activated protein kinase (AMPK)-dependent mechanisms. Yet, the neurochemical identity and neuroanatomical distribution of MBH neurons that express glucoprivic-sensitive AMPK remain unclear. The neurotransmitters γ-aminobutyric acid (GABA) and nitric oxide (NO) act within the MBH to correspondingly inhibit or stimulate glucose counter-regulation. The current review highlights recent findings that GABA and NO, neurons located in the ventromedial hypothalamic nucleus (VMN), a distinct important element of the MBH, are direct targets of noradrenergic regulatory signaling, and thereby, likely operate under the control of hindbrain metabolic-sensory neurons. The ovarian hormone estradiol acts within the VMN to govern energy homeostasis. Discussed here is current evidence that estradiol regulates GABA and NO nerve cell receptivity to norepinephrine and moreover, controls the noradrenergic regulation of AMPK activity in each cell type. Future gains in insight on mechanisms underpinning estradiol’s impact on neurotransmitter communication between the hindbrain and hypothalamic AMPKergic neurons are expected to disclose viable new molecular targets for the therapeutic simulation of hormonal enhancement of neuro-metabolic stability during circumstances of diminished endogenous estrogen secretion or glucose dysregulation.

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Lateral but not Medial Hypothalamic AMPK Activation Occurs at the Hypoglycemic Nadir in Insulin-injected Male Rats: Impact of Caudal Dorsomedial Hindbrain Catecholamine Signaling

Cited by 15 publications

References 46 publications

Sex differences in forebrain estrogen receptor regulation of hypoglycemic patterns of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and astrocyte glycogen metabolic enzyme expression

Sex differences in forebrain estrogen receptor regulation of hypoglycemic patterns of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and astrocyte glycogen metabolic enzyme expression

Hindbrain metabolic deficiency regulates ventromedial hypothalamic nucleus glycogen metabolism and glucose-regulatory signaling

Norepinephrine Regulation of Ventromedial Hypothalamic Nucleus Metabolic-Sensory Neuron 5′-AMP-Activated Protein Kinase Activity: Impact of Estradiol

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