In addition to multiple hypothalamic nuclei, the bed nucleus of the stria terminalis in the forebrain, and the dorsal vagal complex (comprising the dorsal motor nucleus of the vagus nerve, area postrema, and nucleus of the solitary tract) of the hindbrain are implicated in central regulation of glucose homeostasis. Within the hypothalamus, glucose- sensing neurons with intrinsic glucose- responsive characteristics are concentrated in ventromedial, arcuate, and paraventricular nuclei, as well as the lateral hypothalamic area and dorsomedial hypo thalamic nucleus (Figure 1). Glucose- responsive neurons can be broadly classified as either glucose excited (analogous to pancreatic β cells) or glucose inhibited, and are capable of responding to changes in glucose concentrations (e.g. 1–5 mmol/l) that associate with daily fluctuations in brain interstitial fluid glucose homeostasis. What is less clear is the extent to which the activity of these neurons is regulated by physiological variation in brain interstitial fluid glucose. An alternative possibility is that these intrinsic glucose- sensing properties serve as a marker of neurons involved in glucoregulatory neurocircuits, in the same way that many hypothalamic neurons involved in thermoregulation are marked by intrinsic thermosensory properties, even though they do not participate in temperature sensing under physiological conditions. Additional studies are war ranted to sort through these possibilities.
Fig1. Hypothalamic glucoregulatory neurocircuitry implicated in blood glucose control by the brain. Neurons situated in subnuclei spanning the rostral (PVN, paraventricular nucleus; LH, lateral hypothalamic area) and medial (DMN, dorsomedial hypothalamic nucleus; VMN, ventromedial nucleus; ARC, arcuate nucleus; ME, median eminence) hypothalamus are implicated in central control of glucose homeostasis. Melanocortin 4 receptor signalling (M) in neurons in the PVN and elsewhere is stimulated by the agonist α- MSH released by proopiomelanocortin (P, light green) neurons, and inhibited by the inverse agonist agouti- related peptide (A) released by AGRP neurons (A, red) located in the medial ARC region of the mediobasal hypothalamus. AGRP neurons also synapse onto and inhibit proopiomelanocortin (POMC) neurons, and both POMC and AGRP neurons project into the ME, which lacks a fully formed blood–brain barrier, thus allowing subsets of these neurons to sense the circulating glucose level. Source: Figure generated using http:// Biorender.com.
Many defined neuronal subtypes involved in energy and glucose homeostasis have these glucose- sensing properties. The melanocortin system, for example, comprises two arcuate neuronal subsets – proopiomelanocortin (POMC) and agouti- related protein (AGRP) neurons – that mediate opposing effects on downstream neuronal targets that express the melanocortin 4 receptor (MC4R) (Figure 1). Thus, whereas POMC neuron activation induces synaptic release of α- melanocyte- stimulating hormone (αMSH), an MC4R agonist, AGRP is an inverse agonist of MC4R that reduces signalling by this receptor. AGRP neurons also regulate feeding behaviour via release of both neuropeptide Y (NPY) and GABA. AGRP and POMC neurons project to a variety of hypothalamic and extrahypothalamic neurons that express MC4Rs; in the paraventricular nucleus, increased melanocortin signalling reduces food intake while reduced melanocortin signalling (resulting from reduced POMC neuron activity, increased AGRP neuron activity, or both) has the opposite effect.
Among many observations that establish the key role played by melanocortin signalling in energy and glucose homeostasis is the phenotype induced by genetically impaired melanocortin signal ling. Mutations of MC4R, for example, are among the commonest causes of monogenic obesity in humans, and variation at the MC4R gene locus associates with human type 2 diabetes in genome- wide association studies. These phenotypes offer direct evidence of the requirement for intact melanocortin signalling for normal energy and glucose homeostasis.
Importantly, melanocortin signalling is highly responsive to nutritional state owing to coordinated, reciprocal regulation of AGRP and POMC neuron activity by afferent input from leptin and other relevant humoral signals. In response to fasting or other conditions associated with depletion of body fuel stores, for example, AGRP neurons are activated whereas POMC neurons are inhibited, a combination that potently reduces melanocortin signalling and promotes increased food intake, reduced energy expenditure, and recovery of lost weight. These reciprocal neuronal responses are elicited by the effect of fuel depletion to lower circulating levels of leptin, insulin, and glucose, and to increase secretion of the gastric hormone ghrelin. Although some POMC and AGRP neurons qualify as either glucose excited or inhibited, the extent to which these intrinsic glucose- sensing properties drive in vivo responses is unclear.
Another hypothalamic area involved in glucose energy homeostasis is the ventromedial nucleus. Subsets of these neurons constitute a key node in the circuit responsible for mounting counter- regulatory responses to hypoglycaemia. Unexpectedly, a specific subset of these neurons is also implicated in the pathogenesis of hyperglycaemia in diabetic mice. Many ventromedial nucleus neurons are also glucose responsive, but once again, the extent to which the activity of these neurons is determined by intrinsic glucose sensing in vivo (as opposed to afferent input from other neurons in a circuit) awaits further study.
In addition to neurons, many glial cell types are implicated in brain regulation of glucose homeostasis (Figure 2). Astrocytes are the commonest glial cell type in the brain, and direct connections (via gap junctions) exist between these cells and both neurons and other glial cells. Interestingly, gap junction subunits (connexins 30 and 43) expressed by hypothalamic astrocytes appear to be critical for brain glucose sensing and control of insulin secretion during a glucose challenge. This may reflect the fact that astrocytes are essential components of the blood–brain barrier, and are implicated in glucose transport into the brain (via glucose transporter 1 (GLUT1) and possibly GLUT2). Glucose taken up into astrocytes can be metabolized into lactate, which can then be released as a source of fuel for neurons in a process known as the astrocyte–neuron lactate shuttle. Additionally, astrocytes express insulin receptors, deletion of which reduces the responsiveness of POMC neurons to elevated glucose levels.
Fig2. Glucose- sensing cells in the mediobasal hypothalamus. The median eminence (ME) is a circumventricular organ situated at the floor of the mediobasal hypothalamus (MBH) that lacks a fully formed blood–brain barrier. Since the ME is bordered dorsally by the third cerebral ventricle (3V), neurons and glial cell types in this brain area and adjacent arcuate nucleus (ARC) have access to glucose in the bloodstream, in cerebrospinal fluid (CSF) and in brain interstitial fluid (ISF). Cell types capable of sensing glucose include neurons (red and green), astrocytes (purple), and tanycytes (blue). Obesity- associated hypothalamic gliosis is characterized by inflammatory activation of astrocytes (purple) and microglia (green) and is hypothesized to impair both energy and glucose homeostasis, potentially by adversely affecting glucose sensing by cells in this brain area. Source: Figure generated using http://Biorender.com.
Tanycytes are another glial cell type implicated in central nervous system (CNS) glucose sensing (Figure 2). Tanycyte cell bodies line the surface of the third cerebral ventricle, and from there they extend filamentous processes deep into medial hypothalamic structures including the arcuate, ventromedial, and dorsomedial nuclei and median eminence. One proposed role for these cells is to sense and/or transport glucose from the cerebrospinal fluid to these parenchymal areas, but the extent to which tanycytes participate in this type of glucose sensing is unclear. One group found that treatment with alloxan to ablate tanycyte glucose sensing strongly interfered with both counter- regulatory responses to hyperglycaemia and responses to hyperglycaemia, while another group reported that conditional tanycyte ablation pre disposes to obesity and elevated fat mass, but with little effect on glycaemia.
Another noteworthy aspect of hypothalamic glial cells in relation to metabolic diseases pertains to their response to consumption of an obesogenic diet. Rodent studies demonstrate that following the switch to a high- fat diet, reactive gliosis (characterized by inflammatory activation of both astrocytes and microglia) occurs rapidly (within days) in the mediobasal hypothalamus, and that weight gain induced by this diet is limited when this activation response is blocked. Thus, reactive gliosis appears to be required for the full expression of diet- induced obesity in mice. This pathological response is also present in humans with obesity and associates with insulin resistance, even after adjustment for differences of body weight. Microglial mitochondrial dynamics are reportedly involved in this gliosis response; in mice with diet- induced obesity, abnormal POMC neuron responses to hyperglycaemia depend on these microglial changes. Establishing the contribution made by reactive mediobasal hypothalamus gliosis to the pathogenesis of human obesity and type 2 diabetes is an important scientific priority.
Glucose transporters and brain glucose uptake
Members of the GLUT family vary widely with respect to affinity for glucose, transport capacity, tissue distribution, and physiological function. There are 14 known GLUT family members, with one or more being expressed in almost every cell type to facilitate cellular glucose uptake. Table 1 summarizes the characteristics of the different GLUT family members.
Table1. The glucose transporter family.
GLUT1 is a high- affinity, low- capacity glucose transporter, which means that its glucose transport capacity is saturated at concentrations below those usually maintained in the circulation. Consequently, a rise in the plasma glucose level is not typically associated with a proportionate increase in cellular glucose uptake via this transporter. GLUT1 is widely expressed throughout the body, including by endothelial cells and astrocyte processes that form the blood–brain barrier, and is a major transporter for delivery of glucose into the brain. GLUT1 expression in the blood–brain barrier is upregulated under conditions such as hypoxia and hypoglycaemia where neuronal adenosine triphosphate (ATP) generation is compromised as a means to enhance glucose transfer into the brain. Such findings are consistent with glucose transport across the blood–brain barrier by GLUT1 constituting the rate- limiting step in brain glucose delivery. Interestingly, obesity is associated with reduced blood–brain barrier expression of GLUT1 in mice; the finding that hyperglycaemia is associated with reduced brain glucose uptake in people with type 2 diabetes also suggests that similar changes occur in the blood brain barrier of humans with metabolic dysfunction.
GLUT2 is expressed uniquely by cell types specialized for cellular glucose sensing, both in the brain (including glucose- responsive neurons, astrocytes, and tanycytes) and in the periphery (pancreatic β cells, intestinal epithelial cells, hepatocytes, and kidney cells). GLUT2 has a much higher Km for glucose (17 mM) than other glucose transporters, enabling the rate of cellular glucose transport to vary across the full range of extracellular glucose levels. Consequently, this transporter enables changing circulating glucose levels to elicit a proportionate change in cellular uptake. Most cells that express GLUT2 also express glucokinase, an enzyme that, owing to its similarly high Km for glucose (compared to other hexokinase isoforms), enables the rate of glucose phosphorylation to vary with the extracellular glucose level in glucose- sensing cells. While GLUT2 levels in the periphery increase during acutely elevated glycaemia, some insulin- resistant conditions are associated with reduced hypothalamic GLUT2 expression. Furthermore, GLUT2 is implicated in the brain’s ability to mount counter- regulatory responses to hypoglycaemia.
GLUT3 is the predominant GLUT subtype expressed by neurons and is characterized by a lower Km than other neuronal GLUTs, thus enabling efficient neuronal glucose transport from brain interstitial fluid where glucose concentrations are much lower than in the bloodstream. By comparison, GLUT4 is expressed in so- called insulin- sensitive tissues (tissues in which insulin binding to its receptor induces glucose uptake, including adipocytes, cardiomyocytes, and skeletal muscle). Trans location of GLUT4 from the cytosol to the plasma membrane in response to insulin is responsible for insulin- stimulated glucose uptake and associated insulin- mediated glucose clearance from the bloodstream. This mechanism plays a key role in promoting glucose disposal following a meal (e.g. when glucose and insulin levels are elevated). In the brain, GLUT 4 is expressed in distinct populations, including by forebrain cholinergic neurons that also express GLUT3, but the extent to which this GLUT4 is truly insulin responsive and mediates glucose uptake in these neurons awaits further study.
GLUT8 has a low Km for glucose, and its role in cellular glucose uptake remains uncertain, since glucose competes with fructose and galactose for transport via this transporter subtype. In the brain, GLUT8 is expressed by neurons of the hypothalamus, cerebellum, brainstem, and hippocampus, where it is located in proximal and distal dendrites. Like GLUT 4, this transporter resides primarily in the cytosol and is hypothesized to be translocated to the cell surface in response to stimuli that remain to be identified. The extent to which GLUT8 transports other substrates preferentially over glucose also remains to be determined.
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