Hindbrain metabolic deficiency regulates ventromedial hypothalamic nucleus glycogen metabolism and glucose‑regulatory signaling
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.
- Alenazi FSH, Ibrahim BA, Al‑Hamami H, Shakiya M, Briski KP (2016) Role of estradiol in intrinsic hindbrain AMPK regulation of hypothalamic AMPK, metabolic neuropeptide, and norepinephrine activity and food intake in the female rat. Neuroscience 314: 35–46.
- Alhamami HN, Uddin MM, Mahmood ASMH, Briski KP (2018) Lateral but not medial hypothalamic AMPK activation occurs at the hypoglycemic nadir in insulin‑injected male rats: Impact of caudal dorsomedial hind‑ brain catecholamine signaling. Neuroscience 379: 103–114.
- Ali MH, Napit PR, Mahmood ASMH, Bheemanapally K, Alhamami HN, Uddin MM, Mandal KS, Ibrahim MMH, Briski KP (2019) Hindbrain estro‑ gen receptor regulation of ventromedial hypothalamic glycogen metab‑ olism and glucoregulatory transmitter expression in the hypoglycemic male rat. Neuroscience 409: 253–260.
- Bélanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte‑neuron metabolic cooperation. Cell Metab 14: 724–738.
- Beverly JL, de Vries, MG, Beverly MF, Arseneau LM (2000) Norepinephrine mediates glucoprivic‑induced increase in GABA in the ventromedial hypothalamus of rats. Amer J Physiol Regul Integr Comp Physiol 279: R990‑R996.
- Beverly JL, De Vries MG, Bouman SD, Arseneau LM (2001) Noradrener‑ gic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia. Amer J Physiol Regul Integr Comp Physiol 280: R563–569.
- Borg MA, Sherwin RS, Borg WP, Tamborlane WV, Shulman GI (1997) Lo‑ cal ventromedial hypothalamus glucose perfusion blocks counterreg‑ ulation during systemic hypoglycemia in awake rats. J Clin Invest 99: 361–365.
- Borg MA, Tamborlane WV, Shulman GI, Sherwin RS (2003) Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 52: 663–666.
- Briski KP, Mandal SK (2019) Hindbrain lactoprivic regulation of hypotha‑ lamic neuron transactivation and glucoregulatory neurotransmitter expression: Impact of antecedent insulin‑induced hypoglycemia. Neu‑ ropeptides 77: 101962.
- Briski KP, Koshy Cherian A, Genabai NK, Vavaiya KV (2009) In situ coexpres‑ sion of glucose and monocarboxylate transporter mRNAs in metabol‑ ic‑sensitive dorsal vagal complex catecholaminergic neurons: transcrip‑ tional reactivity to insulin‑induced hypoglycemia and caudal hindbrain glucose or lactate repletion during insulin‑induced hypoglycemia. Neu‑ roscience 164: 1152–1160.
- Briski KP, Patil GD (2008) Induction of Fos immunoreactivity labeling in forebrain metabolic loci by caudal fourth ventricular administration of the monocarboxyate transporter inhibitor, α‑cyano‑4‑hydroxycinnamic acid. Neuroendocrinology 82: 49–57.
- Briski KP, Shrestha PK (2016) Hindbrain estrogen receptor‑beta antago‑ nism normalizes reproductive and counter‑regulatory hormone secre‑ tion in hypoglycemic steroid‑primed ovariectomized female rats. Neu‑ roscience 331: 62–71.
- Brown AM (2004) Brain glycogen re‑awakened. J Neurochem 89: 537–552.
- Chan O, Paranjape SA, Horblitt A, Zhu W, Sherwin RS (2013) Lactate‑in‑ duced release of GABA in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes. Diabetes 62: 4239–4246.
- Chan O, Zhu W, Ding Y, McCrimmon RJ, Sherwin RS (2006) Blockade of GAB‑ A(A) receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo‑pituitary‑ad‑ renal response to hypoglycemia. Diabetes 55: 1080–1087.
- Cherian A, Briski KP (2011) Quantitative RT PCR and immunoblot analyses reveal acclimated A2 noradrenergic neuron substrate fuel transporter, glucokinase, phospho‑AMPK, and dopamine‑beta‑hydroxylase respons‑ es to hypoglycemia. J Neurosci Res 89: 1114–1124.
- Dong JH, Chen X, Cui M, Yu X, Pang Q, Sun JP (2012) Β2‑adrenergic receptor and astrocyte glucose metabolism. J Mol Neurosci 48: 456–463.
- Donovan CM, Watts AG (2014) Peripheral and central glucose sensing in hypoglycemic detection. Physiology 29: 314–324.
- Fillenz M, Lowry JP, Boutelle MG, Fray AE (1999) The role of astrocytes and noradrenaline in neuronal glucose metabolism. Acta Physiol Scand 167: 275–284.
- Gruetter R (2003) Glycogen: the forgotten cerebral energy store. J Neurosci Res 74: 179–183.
- Gujar AD, Ibrahim BA, Tamrakar P, Briski KP (2013) Hypoglycemia differ‑ entially regulates hypothalamic glucoregulatory neurotransmitter gene and protein expression: Role of caudal dorsomedial hindbrain catechol‑ aminergic input. Neuropeptides 47: 139–147.
- Gujar AD, Ibrahim BA, Tamrakar P, Koshy Cherian A, Briski KP (2014) Hindbrain lactostasis regulates hypothalamic AMPK activity and hy‑ pothalamic metabolic neurotransmitter mRNA and protein respons‑ es to hypoglycemia. Amer J Physiol Regul Integ Comp Physiol 306: R457‑R469.
- Ibrahim BA, Briski KP (2014) Role of dorsal vagal complex A2 noradrenergic neurons in hindbrain glucoprivic inhibition of the luteinizing hormone surge in the steroid‑primed ovariectomized female rat: Effects of 5‑thio‑ glucose on A2 functional biomarker and AMPK activity. Neuroscience 269: 199–214.
- Ibrahim MMH, Alhamami HN, Briski KP (2019) Norepinephrine regulation of ventromedial hypothalamic nucleus metabolic transmitter biomarker and astrocyte enzyme and receptor expression: role of 5’‑AMP‑activated protein kinase. Brain Research 1711: 48–57.
- Magistretti PJ, Sorg O, Yu N, Martin JL, Pellerin L (1993) Neurotrans‑ mitters regulate energy metabolism in astrocytes: implications for the metabolic trafficking between neural cells. Dev Neurosci 15: 306–312.
- Mahmood ASMH, Bheemanapally K, Mandal SK, Ibrahim MMH, Briski KP (2019) Norepinephrine control of ventromedial hypothalamic nucle‑ us glucoregulatory neurotransmitter expression in the female rat: role of monocarboxylate transporter function. Mol Cell Neurosci 95: 51–58.
- Mandal SK, Briski KP (2018) Hindbrain dorsal vagal complex AMPK controls hypothalamic AMPK activation and metabolic neurotransmitter protein expression and counter‑regulatory hormone secretion in the hypogly‑ cemic male rat. Brain Res Bull 144: 171–179.
- Müller MS, Pedersen SE, Walls AB, Waagepetersen HS, Bak LK (2015) Iso‑ form‑selective regulation of glycogen phosphorylase by energy depriva‑ tion and phosphorylation in astrocytes. Glia 63: 154–162.
- Nadeau OW, Fontes JD, Carlson GM (2018) The regulation of glycogenolysis in the brain. J Biol Chem 293: 7099–7109.
- Napit PR, Ali MH, Shakya M, Mandal SK, Bheemanapally K, Mahmood ASMH, Ibrahim MMH, Briski KP (2019) Hindbrain estrogen receptor regulation of counter‑regulatory hormone secretion and ventromedial hypotha‑ lamic nucleus glycogen content and glucoregulatory transmitter signal‑ ing in hypoglycemic female rats. Neuroscience 411: 211–221.
- Oomura Y, Ono H, Ooyama H, Wayner MJ (1969) Glucose and osmosensi‑ tive neurons of the rat hypothalamus. Nature 222: 282–284.
- Patil GD, Briski KP (2005) Lactate is a critical ‘sensed’ variable in caudal hindbrain monitoring of CNS metabolic stasis. Amer J Physiol Regul Inte‑ gr Physiol 289: R1777–1786.
- Pellerin L, Pellegri G, Bittar PG, Charnay Y, Bouras C, Martin JL (1998) Evi‑ dence supporting the existence of an activity‑dependent astrocyte‑neu‑ ron lactate shuttle. Dev Neurosci 20: 291–299.
- Shakya M, Shrestha PK, Briski KP (2018) Hindbrain 5’‑monophosphate‑acti‑ vated protein kinase mediates short‑term food deprivation inhibition of the gonadotropin‑releasing hormone‑luteinizing hormone axis: role of nitric oxide. Neuroscience 383: 46–59.
- Shrestha PK, Tamrakar P, Ibrahim BA, Briski KP (2014) Hindbrain medulla catecholamine cell group involvement in lactate‑sensitive hypoglyce‑ mia‑associated patterns of hypothalamic norepinephrine and epineph‑ rine activity. Neuroscience 278: 20–30.
- Silver IA, Erecińska M (1998) Glucose‑induced intracellular ion changes in sugar‑sensitive hypothalamic neurons. J Neurophysiol 79: 1733–1745.
- Stobart JL, Anderson CM (2013) Role of astrocytes as gatekeepers of neu‑ ronal energy supply. Front Cell Neurosci 7: 1–21.
- Tamrakar P, Shrestha PK, Briski KP (2015) Dorsomedial hindbrain catechol‑ amine regulation of hypothalamic astrocyte glycogen metabolic enzyme protein expression: Impact of estradiol. Neuroscience 292: 34–45.
- Watts AG, Donovan CM (2010) Sweet talk in the brain: glucosensing, neural networks, and hypoglycemic counterregulation. Front Neuroendocrinol 31: 32–43.