Endocrinol Metab.  2022 Feb;37(1):9-25. 10.3803/EnM.2021.1364.

Homeostatic Regulation of Glucose Metabolism by the Central Nervous System

• Choi JH
• Kim MS

• KMID: 2527133
• DOI: http://doi.org/10.3803/EnM.2021.1364

Abstract

Evidence for involvement of the central nervous system (CNS) in the regulation of glucose metabolism dates back to the 19th century, although the majority of the research on glucose metabolism has focused on the peripheral metabolic organs. Due to recent advances in neuroscience, it has now become clear that the CNS is indeed vital for maintaining glucose homeostasis. To achieve normoglycemia, specific populations of neurons and glia in the hypothalamus sense changes in the blood concentrations of glucose and of glucoregulatory hormones such as insulin, leptin, glucagon-like peptide 1, and glucagon. This information is integrated and transmitted to other areas of the brain where it eventually modulates various processes in glucose metabolism (i.e., hepatic glucose production, glucose uptake in the brown adipose tissue and skeletal muscle, pancreatic insulin and glucagon secretion, renal glucose reabsorption, etc.). Errors in these processes lead to hyper- or hypoglycemia. We here review the current understanding of the brain regulation of glucose metabolism.

Keyword

Glucose; Metabolism; Central nervous system

Figure

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  Fig. 1 Representative neurons and their neural circuits that regulate various aspects of glucose metabolism. (A) The optogenetic and chemogenetic stimulation of Agouti-related protein-expressing (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) decreases systemic insulin sensitivity and glucose tolerance by reducing glucose uptake into brown adipose tissue. These effects are mediated via neural circuits involving the anterior bed nucleus of the stria terminalis (aBNST) and sympathetic nervous system (SNS) [7]. In addition, activation of ARH AgPP neurons may decrease glucose tolerance by increasing hepatic glucose production (HGP) via the vagal pathway [8]. (B) ARH proopiomelanocortin-expressing (POMC) neurons promote renal glucose reabsorption by increasing glucose transporter 2 (GLUT2) expression in the kidney via paraventricular hypothalamus (PVH) melanocortin receptor-4 (MC4R) neurons and SNS. This regulation occurs directly to the kidney and also indirectly through increased circulating epinephrine by increased phenylethanolamine N-methyltransferase (PNMT) expression in the adrenal medulla [11,12]. (C) During hypoglycemia, steroidogenic factor-1 expressing (SF-1) neurons in the ventromedial hypothalamus (VMH) promote HGP through the secretion of counterregulatory hormones (e.g., glucagon and corticosterone) [14], while they improve insulin sensitivity by increasing glucose uptake in skeletal muscle via the central melanocortin system−SNS [15,16]. ACTH, adrenocorticotropic hormone; DVC, dorsal vagal complex; LV, lateral ventricle; 4V, fourth ventricle.

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  Fig. 2 Molecular mechanisms of glucose-sensing in hypothalamic neurons, tanycytes, and perivascular macrophages. (A) Proposed glucose-sensing mechanisms in hypothalamic neurons. In glucose-excitatory (GE) neurons, glucose enters the neuron through glucose transporter (GLUT) 2/3/4 and increases the intracellular adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio, resulting in the closure of ATP-dependent potassium channel (KATP), depolarization of membrane potential, Ca2+ influx through voltage-dependent calcium channel (VDCC), finally releasing neurotransmitter (left panel) [36]. Similarly to GE neuron, glucose enters glucose-inhibitory (GI) neuron through GLUT2/3/4 and increases the intracellular ATP/adenosine monophosphate (AMP) ratio. However, this event leads to inhibition of neuronal activity in GI neurons possibly through stimulation of the Na+/K+-ATPase activity or opening of Cl− channels through suppression of adenosine monophosphate kinase (AMPK) and nitric oxide (NO) production (right panel) [44,46]. Modified from Pozo et al. [33]. (B) Glucose-sensing mechanisms mediated by hypothalamic tanycytes. Glucose enters hypothalamic tanycytes via GLUT2 and converts to lactate via glucokinase (GK) and lactate dehydrogenase (LDH). Tanycyte-produced lactate is released via monocarboxylate transporter (MCT) 1/4 and taken by adjacent neurons via MCT2. In the GE neuron, lactate converts to pyruvate, that produces ATP, and depolarizes neuron action potential via inhibition of KATP channels. Modified from Elizondo-Vega et al. [64]. (C) Perivascular macrophages (PVMs) reside in the Virchow-Robin space regulate glucose flux across the blood-brain barrier (BBB). Glucose flux into the brain decreases upon 3 days-consumption of high-fat diet (HFD) in mice. However, during prolonged HFD feeding (28 days), the PVMs secrete vascular endothelial growth factor (VEGF), which stimulates endothelial GLUT1 expression and thereby restores reduced glucose flux. ARH, arcuate hypothalamus; CLC, chloride channel; G-6-P, glucose-6-phosphate; ME, median eminence; NT, neurotransmitter; 3V, third ventricle; VMH, ventromedial hypothalamus.

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  Fig. 3 Insulin signaling in hypothalamic neurons and astrocytes regulates systemic glucose metabolism. (A) Insulin signaling in hypothalamic Agouti-related protein (AgRP) and dorsal motor nucleus of the vagus (DMV) neurons. In these neurons, insulin inhibits neuronal activity through the phosphatidyl-inositol-3 kinase (PI3K)- and extracellular signal-regulated kinase (ERK)-dependent opening of ATP-dependent potassium (KATP) channels [72,73]. Activated insulin signaling in AgRP neurons inhibits hepatic glucose production (HGP) [74] and stimulates glucose-stimulated insulin secretion (GSIS) from the pancreatic β-cells [78]. (B) Overnutrition causes hyperinsulinemia, a condition that adversely affects glucose homeostasis through its effects on specific hypothalamic neurons [83]. The activation of insulin signaling in lateral hypothalamus (LH) melanin-concentrating hormone (MCH) neurons decreases hepatic insulin sensitivity [85]. Insulin signaling in ventromedial hypothalamus (VMH) steroidogenic factor-1 expressing (SF-1) neurons promotes obesity and glucose dysregulation by inhibiting SF-1 neuronal activity [86]. Enhanced insulin signaling in developing proopiomelanocortin (POMC) neurons suppresses GSIS by reducing POMC axonal projections to the paraventricular hypothalamus (PVH) and the parasympathetic innervation of pancreatic islets [84]. (C) Astrocytic insulin signaling stimulates the glucose flux into the hypothalamus by increasing blood-brain barrier (BBB) glucose transporter 1 (GLUT1) expression. This helps POMC neurons to generate satiety and stimulate GSIS [87]. Modified from Garcia-Caceres et al. [87]. α7-nAchR, α7 nicotinic acetylcholine receptor; Ach, acetylcholine; ARH, arcuate nucleus of the hypothalamus; DVC, dorsal vagal complex; IL-6, interleukin-6; IR, insulin receptor; IRS, insulin receptor substrate; JAK, Janus kinase; MEK, mitogen-activated protein kinase; PIP2, phosphatidyl-inositol diphosphate; PIP3, phosphatidyl-inositol triphosphate; SNS, sympathetic nervous system; STAT3, signal transducer and activator of transcription 3.

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  Fig. 4 Hormonal (leptin, glucagon-like peptide 1 [GLP-1], and glucagon) signaling modulates peripheral glucose metabolism via central actions. (A) Leptin signaling in both the arcuate nucleus of the hypothalamus (ARH) proopiomelanocortin-expressing neuron (POMC) and the ventromedial hypothalamus (VMH) neurons leads to decreased hepatic glucose production (HGP) and increased insulin-independent glucose uptake in the brain, skeletal muscle, and brown adipose tissue (BAT) [88]. By acting on VMH neurons, leptin stimulates skeletal muscle glucose uptake via the central melanocortin receptor−sympathetic nervous system (SNS)−skeletal muscle AMP-activated protein kinase (AMPK) signaling mechanism [16,91,92]. (B) GLP-1 increases glucose-stimulated insulin secretion (GSIS) but inhibits HGP through GLP-1 receptor signaling in the ARH [93]. Glucagon enhances HGP via a direct action on hepatocytes whereas it acts on the hypothalamus to inhibit HGP [94]. AC, adenylyl cyclase; ACC, acetyl-CoA carboxylase; α-AR, α-adrenergic receptor; α2-AMPK, α2-catalytic subunit of adenosine monophosphate kinase; β2-AR, β2-adrenergic receptor; GLP-1R, GLP-1 receptor; I3K, phosphatidyl-inositol-3 kinase; GR, glucagon receptor; IRS, insulin receptor substrate; KATP, ATP-dependent potassium channel; LepR, leptin receptor; PKA, protein kinase A.

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  Fig. 5 Obesity-induced hypothalamic inflammation and its possible impacts on glucose homeostasis. Overnutrition causes inflammation in the arcuate nucleus of the hypothalamus (ARH), which is mediated by activated microglia, perivascular macrophages (PVMs), and reactive astrocytes [96–99]. Upon persistent exposure to fat-rich diets, these glial cells secrete proinflammatory cytokines and reactive oxygen species (ROS), thereby activating inflammatory signaling pathways and disrupting leptin and insulin signaling in adjacent neurons [99]. Activation of inducible nitric oxide synthase (iNOS) in hypothalamic PVMs increases the permeability of the blood-brain barrier (BBB), which results in increased fatty acid flux into the ARH and accelerated fatty acid-induced hypothalamic inflammation [99]. NF-κB, nuclear factor kappa B; GFAP, glial fibrillary acidic protein; NO, nitric oxide.

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