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

Karen P Briski,Santosh K Mandal

doi:10.21307/ane-2020-006

Karen P Briski, Santosh K Mandal

Open Access

https://doi.org/10.21307/ane-2020-006

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Abstract

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.

Highlights

The ventromedial hypothalamic nucleus (VMN) utilizes metabolic sensory information in the form of nutrient, endocrine, and neurochemical cues to direct glucose counter‐regulatory motor functions (Watts and Donovan, 2010; 2014)
We reported that VMN astrocytes express nor‐ epinephrine (NE)‐sensitive alpha1 (α1), al‐ pha2 (α2) and beta1 (β1) adrenergic receptor (AR) pro‐ teins, and that NE inhibits net VMN glycogen phosphorylase (GP) content (Ibra‐ him et al, 2019)
Our work shows that exogenous NE causes coincident up‐regulation of VMN GPbb and GAD65/67, and that the latter response is abolished by interruption of astrocyte substrate fuel provision (Mahmood et al, 2019)

Summary

Introduction

The ventromedial hypothalamic nucleus (VMN) utilizes metabolic sensory information in the form of nutrient, endocrine, and neurochemical cues to direct glucose counter‐regulatory motor functions (Watts and Donovan, 2010; 2014). The VMN and other hypothalamic glucose‐reg‐ ulatory loci receive vital metabolic sensory input. Dorsal vagal complex (DVC) A2 noradrenergic neurons are a likely source of such communication as these cells express hypo‐ glycemia‐sensitive metabolic sensory biomarkers, e.g., glucokinase, KATP, and 5’‐AMP‐activated protein kinase (AMPK) (Briski et al, 2009; Cherian and Briski, 2011). DVC lactate deficiency acti‐ vates A2 neurons (Patil and Briski, 2005) and increas‐ es hypothalamic NE activity (Shrestha et al, 2014). A subset of subjects in each treatment group were pretreated by intra‐CV4 delivery of the selective catecholamine neurotoxin 6‐hydroxydopa‐ mine (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 GAD65/67

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