Norepinephrine Regulation of Ventromedial Hypothalamic Nucleus Astrocyte Glycogen Metabolism

Abstract

The catecholamine norepinephrine (NE) links hindbrain metabolic-sensory neurons with key glucostatic control structures in the brain, including the ventromedial hypothalamic nucleus (VMN). In the brain, the glycogen reserve is maintained within the astrocyte cell compartment as an alternative energy source to blood-derived glucose. VMN astrocytes are direct targets for metabolic stimulus-driven noradrenergic signaling due to their adrenergic receptor expression (AR). The current review discusses recent affirmative evidence that neuro-metabolic stability in the VMN may be shaped by NE influence on astrocyte glycogen metabolism and glycogen-derived substrate fuel supply. Noradrenergic modulation of estrogen receptor (ER) control of VMN glycogen phosphorylase (GP) isoform expression supports the interaction of catecholamine and estradiol signals in shaping the physiological stimulus-specific control of astrocyte glycogen mobilization. Sex-dimorphic NE control of glycogen synthase and GP brain versus muscle type proteins may be due, in part, to the dissimilar noradrenergic governance of astrocyte AR and ER variant profiles in males versus females. Forthcoming advances in the understanding of the molecular mechanistic framework for catecholamine stimulus integration with other regulatory inputs to VMN astrocytes will undoubtedly reveal useful new molecular targets in each sex for glycogen mediated defense of neuronal metabolic equilibrium during neuro-glucopenia.

Keywords: adrenergic receptor; glycogen phosphorylase brain type; laser-catapult microdissection; norepinephrine; ventromedial hypothalamic nucleus.

Figure 1

Differential hindbrain noradrenergic regulation of the ventromedial hypothalamic nucleus (VMN) glycogen phosphorylase brain (GPbb) versus muscle (GPmm) type protein expression. The coronal brain section illustration at the top depicts the location of the VMN within the mediobasal hypothalamus; that area is enlarged in the blue rectangle to show micropunch tool positioning for the collection of VMN tissue for the Western blot analysis of GPmm and GPbb proteins. The hollow circular punch tool was centered on the longitudinal axis of the VMN to acquire tissue from dorsomedial (dm), central (c) and ventrolateral regions of this nucleus. In the brain, GP proteins are expressed primarily in astrocytes but neurons also contain GPbb, albeit at relatively lower levels. Male rats were pretreated by the administration of vehicle (V) or the catecholamine neurotoxin 6-hydroxydopamine (6OHDA) into the caudal fourth ventricle (CV4) prior to the delivery of the monocarboxylate transporter inhibitor 4-alpha-cyano-cinnamic acid (4CIN). At the bottom, the arrows indicate the direction of various treatment effects on GPmm (left) and GPbb (right) expression relative to V-treated controls.

Figure 2

Norepinephrine (NE) regulation of the hypothalamic astrocyte glycogen metabolic enzyme and adrenergic and estrogen receptor variant protein expression and glycogen content in male versus female primary hypothalamic astrocyte cell cultures. In each graph, tick marks along the x axis indicate, from right to left, astrocyte incubation with NE over a dosage range of 0, 0.1, 1.0, 10.0, 100.0 or 1000 nM. Abbreviations: α₁-AR: alpha₁-adrenergic receptor; α₂-AR: alpha₂-adrenergic receptor; β₁-AR: beta₁-adrenergic receptor; β₂-AR: beta₂-adrenergic receptor; AMPK: 5′-AMP-activated protein kinase; CaMMKB: calcium/calmodulin-dependent protein kinase kinase-β; ERα: estrogen receptor-alpha; ERβ: estrogen receptor-beta; GS: glycogen synthase; GPbb: glycogen phosphorylase brain type; GPER: G-protein-coupled estrogen receptor-1; GPmm: glycogen phosphorylase muscle type; pAMPK: phosphoAMPK; pGS: phosphoGS; PP1: protein phosphatase-1.