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Brain Glucose-Sensing Mechanism and Energy Homeostasis

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Abstract

The metabolic and energy state of the organism depends largely on the availability of substrates, such as glucose for ATP production, necessary for maintaining physiological functions. Deregulation in glucose levels leads to the appearance of pathological signs that result in failures in the cardiovascular system and various diseases, such as diabetes, obesity, nephropathy, and neuropathy. Particularly, the brain relies on glucose as fuel for the normal development of neuronal activity. Regions adjacent to the cerebral ventricles, such as the hypothalamus and brainstem, exercise central control in energy homeostasis. These centers house nuclei of neurons whose excitatory activity is sensitive to changes in glucose levels. Determining the different detection mechanisms, the phenotype of neurosecretion, and neural connections involving glucose-sensitive neurons is essential to understanding the response to hypoglycemia through modulation of food intake, thermogenesis, and activation of sympathetic and parasympathetic branches, inducing glucagon and epinephrine secretion and other hypothalamic-pituitary axis-dependent counterregulatory hormones, such as glucocorticoids and growth hormone. The aim of this review focuses on integrating the current understanding of various glucose-sensing mechanisms described in the brain, thereby establishing a relationship between neuroanatomy and control of physiological processes involved in both metabolic and energy balance. This will advance the understanding of increasingly prevalent diseases in the modern world, especially diabetes, and emphasize patterns that regulate and stimulate intake, thermogenesis, and the overall synergistic effect of the neuroendocrine system.

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Abbreviations

2-DG:

2-Deoxyglucose

5-TG:

5-Thioglucose

ACTH:

Adrenocorticotropic hormone

ADP:

Adenosine diphosphate

AgRP:

Agouti-related Protein

AICAR:

5-Aminoimidazole-4-carboxamide ribonucleotide

AMP:

Adenosine monophosphate

AMPK:

AMP-activated protein kinase

ANS:

Autonomic nervous system

AP:

Area postrema

ARC:

Arcuate nucleus

ATP:

Adenosine triphosphate

BAT:

Brown adipose tissue

BDNF:

Brain-derived neurotrophic factor

CART:

Cocaine- and anfetamine-regulated transcript peptide

CFTR:

Cystic fibrosis transmembrane regulator

cGMP:

Guanosine monophosphate

CRH:

Corticotropin-releasing hormone

CSF:

Cerebrospinal fluid

Cx43-HC:

Connexin 43 hemichannel

DBI:

Diazepam-binding inhibitor

DMN:

Dorsomedial nucleus of the hypothalamus

DMV:

Dorsal motor nucleus of the Vagus Nerve

ES:

Endocrine system

F-2,6-P:

Fructose-2,6-bisphosphate

F-6-P:

Fructose 6-phosphate

G-6-P:

Glucose 6-phosphate

GABA:

γ-Aminobutyric acid

GE:

Glucose-excited

GH:

Growth hormone

GI:

Glucose-inhibited

GK:

Glucokinase

GLUT:

Glucose transporter

ICV:

Intracerebroventricular

IP3:

Inositol triphosphate

IP3R3:

IP3-activated Ca2+ channel

K2P:

Tow-pore domain K+ channel

KATP :

ATP-sensitive K+ channel

LC:

Locus coeruleus

LH:

Lateral hypothalamus

MCH:

Melanin-concentrating hormone

MCHR:

MCH receptor

MCR:

Melanocortin receptor

MCT:

Monocarboxylate transporter

ME:

Median eminence

MSH:

Melanocyte-stimulating hormone

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NPY:

Neuropeptide Y

NTS:

Nucleus of the solitary tract

ODN:

Octadecaneuropeptide

Ox:

Orexin

OXT:

Oxytocin

P2Y1:

Purinergic receptor

PANS:

Parasympathetic autonomic nervous system

PBN::

Parabrachial nucleus

PFK:

Phosphofructokinase

PIP2:

Phosphatidylinositol-2-phosphate

POMC:

Proopiomelanocortin

PVN:

Paraventricular nucleus of the hypothalamus

ROS:

Reactive oxygen species

RVLM:

Rostral ventrolateral region of the medulla oblongata

SANS:

Sympathetic autonomic nervous system

SF1:

Steroidogenic factor 1

sGC:

Soluble guanylate cyclase

SGLT:

Sodium-glucose cotransporter

SUR1:

Sulfonyurea receptor 1

SVCT:

Sodium-dependent vitamin C transporter

T1R:

Taste receptor subunit

T3 :

Triiodothyronine

T4 :

Tetraiodothyronine

TCA:

Tricarboxylic acid cycle

TRH:

Thyrotropin-releasing hormone

Trpm5:

Transient receptor potential cation channel subfamily M member 5

TSH:

Thyroid-stimulating hormone

UCP:

Uncoupling protein

VDCC:

Voltage-dependent calcium channel

VGKC:

Voltage-gated K+ channels

vGLUT:

Vesicular glutamate transporter

VMN:

Ventromedial nucleus of the hypothalamus

Y:

Neuropeptide Y receptor

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Acknowledgements

This work was supported by FONDECYT Initiation into Research grant Fondecyt 11150678 (Fernando MartÍnez), Fondecyt 11140405 (Katterine Salazar), Fondecyt 1181243 (Francisco Nualart), and a CONICYT PIA ECM-12 grant (Francisco Nualart). The funders had no role in the study design, data collection, data analysis, decision to publish, or preparation of the manuscript.

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López-Gambero, A.J., Martínez, F., Salazar, K. et al. Brain Glucose-Sensing Mechanism and Energy Homeostasis. Mol Neurobiol 56, 769–796 (2019). https://doi.org/10.1007/s12035-018-1099-4

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  • DOI: https://doi.org/10.1007/s12035-018-1099-4

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