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Hot Topic Reviews |
1 Department of Cell Biology, Division of Medicine, Faculty of Medicine, Sir Alexander Fleming Building, Exhibition Road, Imperial College London, London, UK
Abstract
A fuller understanding of the central mechanisms involved in controlling food intake and metabolism is likely to be crucial for developing treatments to combat the growing problem of obesity in Westernised societies. Within the hypothalamus, specialized neurones respond to both appetite-regulating hormones and circulating metabolites to regulate feeding behaviour accordingly. Thus, the activity of hypothalamic glucose-excited and glucose-inhibited neurones is increased or decreased, respectively, by an increase in local glucose concentration. These ‘glucose-sensing’ neurones may therefore play a key role in the central regulation of food intake and potentially in the regulation of blood glucose concentrations. Whilst the intracellular signalling mechanisms through which glucose-sensing neurones detect changes in the concentration of the sugar have been investigated quite extensively, many elements remain poorly understood. Furthermore, the similarities, or otherwise, with other nutrient-sensing cells, including pancreatic islet cells, are not completely resolved. In this review, we discuss recent advances in this field and explore the potential involvement of AMP-activated protein kinase and other nutrient-regulated protein kinases.
(Received 4 October 2006;
accepted after revision 1 December 2006; first published online 7 December 2006)
Corresponding author G. A. Rutter: Department of Cell Biology, Division of Medicine, Faculty of Medicine, Sir Alexander Fleming Building, Exhibition Road, Imperial College London, London SW7 2AZ, UK. Email: g.rutter{at}imperial.ac.uk
Clinical obesity, an important risk factor for the development of type 2 diabetes, now affects approximately 30% of the US and 20% of the UK adult populations (Marx, 2003; Grundy et al. 2004). The investigation of the mechanisms involved in the central control of satiety and metabolism is therefore crucial to improve treatments for obese patients.
Neurones of the hypothalamic arcuate nucleus (ARC) that express neuropeptide Y (NPY) and agouti-related peptide, or pro-opiomelanocortin (POMC) and cocaine–amphetamine-regulated transcript (Fig. 1), have been identified as key components in the central control of satiety (Marx, 2003). These neurones are targeted by several appetite-regulating hormones, including leptin (Elias et al. 1999; Cowley et al. 2001; Jobst et al. 2004) and ghrelin (Cowley et al. 2003). In addition, changes in circulating blood glucose concentration also exert direct effects on the electrical activity of neurones within this region (Oomura et al. 1969, 1974).
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Here, we will concentrate on the acute regulation of electrical activity of cells in these brain regions, and compare the mechanisms involved with those which appear to mediate the effects of glucose on pancreatic islet 
- and ß-cells (Rutter, 2004).
Functions of hypothalamic glucose-sensing neurones
Glucose infusions into the hypothalamus lead to a decrease in food intake and body weight in rodents (Davis et al. 1981; Panksepp & Rossi, 1981; Kurata et al. 1986), suggesting that one of the functions of hypothalamic glucose sensing is appetite control. Furthermore, NPY and POMC hypothalamic neurones, implicated by other means (Clark et al. 1984; Chronwall et al. 1985; Marx, 2003) in the control of feeding, have been shown to respond to changes in glucose concentration (Muroya et al. 1999; Muroya et al. 2001; Ibrahim et al. 2003; Burdakov et al. 2005). Moreover, intracerebroventricular or intrahypothalamic administration of glucose causes a subsequent inhibition of hepatic glucose output, suggesting that glucose-sensing neurones are also likely to be involved in regulating blood glucose concentrations (Lam et al. 2005). Finally, glucose-sensing neurones are also likely to be important in initiating counter-regulatory responses to raise blood glucose levels (Levin, 2002; Evans et al. 2004).
Glucose sensitivity of hypothalamic glucose-sensing neurones
The glucose concentrations to which hypothalamic glucose-sensing neurones are normally exposed remain controversial. There is evidence to suggest that hypothalamic glucose concentrations are similar to those in the rest of the brain, and may be as low as 20–30% of those found in the blood. Thus, experiments using glucose-sensitive microelectrodes have measured brain glucose concentrations of 0.2–4.2 mmol l–1, as blood glucose concentrations varied over the range 1.6–17.6 mmol l–1 (Silver & Erecinska, 1994, 1998). Wang et al. (2004) recently sought to explore the glucose sensitivity of ARC GE neurones directly by investigating the electrical activity of these cells over glucose concentrations ranging from 0 to 10 mmol l–1. Thus, GE neurones showed the greatest sensitivity to changes in glucose concentration at glucose concentrations of < 2 mmol l–1 (Wang et al. 2004). These results and others (Burdakov et al. 2006) support the hypothesis that these neurones are exposed to glucose concentrations similar to those found in other areas of the brain.
However, the location of glucose-sensing neurones in the ARC and VMN areas (see Fig. 1) of the hypothalamus means that they are in close association with the median eminence, a region where the blood–brain barrier is more permeable than usual owing to a highly vascularized local capillary network (Ganong, 2000). These specialist hypothalamic neurones might therefore be exposed to higher glucose concentrations than neurones in deeper brain regions (Spanswick et al. 1997; Ganong, 2000; Mobbs et al. 2001; Ainscow et al. 2002; Fioramonti et al. 2004). The likely involvement of glucokinase (GK) in hypothalamic glucose sensing (Dunn-Meynell et al. 2002) might also indicate that glucose-sensing neurones are exposed to higher glucose concentrations than other brain areas, given that the Km for glucose of this enzyme is 8–15 mmol l–1 (Matschinsky et al. 1998; Roncero et al. 2000).
The determination of the physiological glucose concentrations to which these glucose-sensing neurones are exposed in vivo remains an important issue for future studies.
Neuropeptide phenotype of glucose-sensing neurones
Glucose-excited neurones. Studies using transgenic POMC-green fluorescent protein (GFP) mice showed that ARC POMC neurones displayed typical GE responses and expressed the KATP channel (Ibrahim et al. 2003), indicating that the GE neurone population may overlap with the ARC POMC-expressing neuronal population. However, other studies using postexperimental labelling of ARC GE neurones showed that these neurones were not positive for POMC (Wang et al. 2004). Additional studies may therefore be required to confirm the presence of POMC-expressing GE neurones in this region of the hypothalamus.
It has recently been reported that melanin-concentrating hormone (MCH)-expressing neurones in the LH are stimulated by increases in glucose concentration (Burdakov et al. 2005), suggesting that these MCH neurones may form a further subpopulation of GE neurones that resides in the LH.
It will be important for future studies to investigate the possible neuropeptide phenotypes of GE neurones which express neither POMC nor MCH, in order to fully elucidate the possible physiological roles of GE neurones in vivo.
Glucose-inhibited neurones. A population of GI neurones in the basomedial hypothalamus has been shown to express NPY, both through immunocytochemistry (Muroya et al. 1999) and through the use of a neuropeptide Y promoter-driven adenovirally expressed ratiometric ‘pericam’ (a GFP-based Ca2+ sensor; Mountjoy et al. 2007). In the latter study, NPY neurones were identified through the expression of the targeted fluorescent protein, and the responses to glucose investigated by imaging cytosolic free Ca2+ concentration (Fig. 2; Mountjoy et al. 2007). In addition, LH orexin neurones have also been identified as being GI-type neurones (Muroya et al. 2001; Yamanaka et al. 2003; Burdakov et al. 2005). It should be noted, however, that another study found that LH orexin neurones and GI neurones represented distinct populations of cells (Liu et al. 2001).
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Mechanisms of glucose detection by hypothalamic glucose-sensing neurones
Glucose-excited neurones: ‘ß-cells’ in the brain?. The presence in GE neurones of GK (Dunn-Meynell et al. 2002; Kang et al. 2004, 2006) and of ATP-sensitive potassium (KATP) channels composed of Kir6.2 and SUR1 subunits (Ashford et al. 1990; Kang et al. 2004) led to the proposal that these cells sense changes in the concentration of glucose via a mechanism analogous to that which operates in pancreatic ß-cells (Rutter, 2004). In the latter, increased glucose concentrations are detected primarily through increased oxidation of glucose and generation of ATP (Panten et al. 1973), and subsequent changes in electrical activity caused by closure of KATP channels (Ashcroft et al. 1984).
Consequently, closure of KATP channels and increased electrical activity in response to elevated glucose concentrations have also been identified in a population of hypothalamic GE neurones (Ashford et al. 1990; Spanswick et al. 1997; Song et al. 2001). Of note, the closure of KATP channels may also involve increased release of lactate from neighbouring glial cells as glucose concentrations rise, followed by an increase in the conversion of lactate to pyruvate in GE neurones (Ainscow et al. 2002; Lam et al. 2005). Importantly, levels of the lactate/monocarboxylate transporter MCT-1, which are very low in pancreatic ß-cells (Sekine et al. 1994; Ishihara et al. 1999; Cohen et al. 2001), appear to be relatively high in the hypothalamus (Ainscow et al. 2002), and may allow lactate to serve as a regulator of GE (or GI) neurones. Nevertheless, careful analysis of the levels of MCT-1 expression at the level of individual neurones in this brain region, and correlation with responses to glucose and/or lactate, has yet to be performed.
Studies using Kir6.2 knockout mice support an involvement of KATP channels in either the development of, or glucose sensing by, GE neurones (Miki et al. 2001). Thus, GE neurones were completely absent from the VMN of Kir6.2–/– mice. Furthermore, these mice displayed impaired glucagon secretion in response to a peripheral hypoglycaemia (Miki et al. 2001), highlighting the importance of GE neurones in the counter-regulatory response to hypoglycaemia. Similar results have since been obtained using KATP channel blockers (Evans et al. 2004). In addition, Kir6.2–/– mice also showed suppressed food intake in response to neuroglycopenia (Miki et al. 2001), providing further evidence of a role for KATP-expressing neurones in the control of food intake.
Recent studies have suggested that a further population of GE neurones may sense glucose independently of changes in KATP channel activity. Thus, glucose-induced increases in intracellular free ATP concentrations are considerably smaller in hypothalamic neurones than in pancreatic ß-cells (Ainscow et al. 2002), complicating the proposed role of changes in KATP channel activity in GE neurones. Furthermore, a KATP channel-independent glucose-sensing mechanism has been identified in a population of ARC GE neurones (Fioramonti et al. 2004), which is proposed to involve cell depolarization resulting from the opening of a non-specific cation channel at elevated glucose concentrations. Importantly, this mechanism continued to operate in GE neurones from the ARC of KATP channel-deficient Kir6.2–/– mice.
The primary glucose transporter in GE neurones seems likely to be GLUT3, rather than the GLUT2 transporters (or possibly GLUT1 in man) present in pancreatic ß-cells (Kang et al. 2004). Since GLUT3 is expected to be saturated at brain glucose concentrations (Kang et al. 2004), glucose transport into GE neurones is unlikely to be involved in the responses of these neurones to elevated glucose concentrations. In contrast, the glycolytic enzyme GK is likely to be involved in the glucose-sensing mechanism of hypothalamic GE neurones, consistent with its involvement in pancreatic ß-cells (Dunn-Meynell et al. 2002; Kang et al. 2004, 2006). Thus, pharmacological (Dunn-Meynell et al. 2002; Kang et al. 2006) and genetic manipulation (Kang et al. 2006) of GK activity have been shown to regulate the responses of hypothalamic GE neurones.
Changes in AMP-activated protein kinase (AMPK) activity were also recently implicated in the control of food intake in living rodents (Andersson et al. 2004; Minokoshi et al. 2004). AMPK, which has previously been described as a ‘fuel gauge’ for mammalian cells, is normally activated under conditions which induce low cellular energy levels and thus increase the ratio of AMP to ATP (Hardie et al. 1998; Rutter et al. 2003). Nevertheless, very recent studies showed that, in contrast to the situation in pancreatic ß-cells (Salt et al. 1998; da Silva Xavier et al. 2000, 2003), the KATP channel-independent effects of glucose on GE neurones were unlikely to involve changes in AMPK activity (Mountjoy et al. 2007).
These potential mechanisms of glucose sensing in GE neurones are summarized in Fig. 3.
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-cells’ in the brain?.
The mechanisms through which hypothalamic GI neurones sense glucose are not as well characterized as those for GE neurones. A priori, it might be predicted that some of the same mechanisms may operate in GI neurones as in pancreatic islet -cells (Ravier & Rutter, 2005), since electrical activity and Ca2+ oscillations are inhibited in response to high glucose in both cell types. Although subtle changes in KATP channel activity are implicated in -cells (Gromada et al. 2004), it appears unlikely that changes in KATP channel activity are involved in mediating the effects of glucose on the majority of GI neurones. Instead, an early study proposed that the effects of glucose on LH GI neurones may be mediated by changes in the activity of the electrogenic Na+–K+ pump (Oomura et al. 1974). In contrast, a very recent study showed that LH GI neurones expressing orexin, another neuropeptide involved in controlling appetite, were inhibited by glucose through a mechanism involving changes in the activity of plasma membrane tandem-pore K+ (TASK) channels (Burdakov et al. 2006), a report which, importantly, demonstrated glucose sensitivity in the range 1–2.5 mM, possibly representing the physiological range of glucose concentrations in the ventromedial hypothalamus. Changes in intracellular free ATP or Ca2+ concentrations were unlikely to be involved in the latter mechanism, since manipulation of the concentrations of these molecules did not affect the responses of these cells to glucose (Burdakov et al. 2006). A further study indicated that the opening of plasma membrane Cl– channels at elevated glucose concentrations may lead to cell hyperpolarization and inhibition of VMN hypothalamic GI neurones (Song et al. 2001). As with GE neurones, changes in glucose transport through GLUT3 are unlikely to be involved in this glucose-sensing mechanism, whilst GK is again implicated in the regulation of GI neurones by glucose (Dunn-Meynell et al. 2002; Kang et al. 2006).
In contrast to GE neurones, changes in AMPK activity are likely to mediate the effects of glucose on basomedial hypothalamic GI neurones (Mountjoy et al. 2007), a proportion of which express NPY (Mountjoy et al. 2007). These findings raise the possibility that NPY-expressing GI neurones could play a role in the recently identified effects of AMPK activation or inhibition on satiety and feeding in vivo (Andersson et al. 2004; Minokoshi et al. 2004). Thus, it has been proposed that AMPK may be involved in the activation of basomedial hypothalamic GI neurones at low glucose concentrations via the following mechanism (Fig. 4). At low [glucose], the rate of sugar uptake through GLUT3 (Kang et al. 2004), and metabolism through GK and the glycolytic pathway (Dunn-Meynell et al. 2002; Kang et al. 2006), would fall. The resulting increase in the AMP:ATP ratio would then lead to an activation of AMPK. It is possible that AMPK may then act to directly phosphorylate and inactivate plasma membrane Cl– and possibly other ion channels (Song et al. 2001), leading to cell depolarization, and activation of the neurones. Enhanced release of the orexigenic peptide NPY from some GI neurones could act via a series of ‘second-order’ neurones to regulate cerebral cortex and autonomic preganglionic neurones involved in controlling feeding behaviour (Elias et al. 1999), and possibly affect counter-regulatory responses to regulate blood glucose levels (McCrimmon et al. 2004). Importantly, these findings of a role for AMPK in GI neurones are reminiscent of a role in ß-cells, as discussed above (Salt et al. 1998; da Silva Xavier et al. 2000, 2003; Richards et al. 2005), and also in -cells (G. A. Rutter, E. Fernandez-Millan, I. Leclerc & G. da Silva Xavier, unpublished observations), where, interestingly, activation of AMPK appears to be required for glucagon release. Interestingly, this is in contrast to the situation in ß-cells, where active AMPK appears to inhibit insulin release. Whether other members of the nutrient-regulated kinase family, such as per-arnt-sim (PAS)-domain kinase (PASK; da Silva Xavier et al. 2004), also play a role in the brain may deserve further attention.
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Response of hypothalamic glucose-sensing neurones to hormonal stimuli
Both GE and GI neurones within the hypothalamus are also responsive to key peripheral feeding hormones. Spanswick et al. (1997) reported that leptin inhibited both VMN and ARC hypothalamic GE neurones by activating KATP channels and hyperpolarization. In contrast, Wang et al. (2004) found that ARC GE neurones were unresponsive to leptin, whilst again identifying an inhibitory effect of leptin on VMN hypothalamic GE neurones. Another study has also identified a population of GE neurones in the VMN which were activated by leptin (Muroya et al. 2004). These variations in the responses of GE neurones to leptin suggest that there may be several different subpopulations of GE neurones in the hypothalamus, with differing physiological responses and functions.
Leptin has been shown to inhibit the majority of GI neurones (Funahashi et al. 1999; Mountjoy et al. 2007), possibly through a mechanism involving leptin-induced inhibition of AMPK (Mountjoy et al. 2007). In contrast, ghrelin, in common with the action of low glucose concentrations, activates ARC GI neurones (Kohno et al. 2003). Finally, the importance of leptin signalling in glucose-sensing neurones during the control of food intake and blood glucose concentrations was recently shown by experiments using an obese, hyperglycaemic, leptin receptor-deficient mouse model (Coppari et al. 2005). Re-activation of the leptin receptor specifically in the ARC of these leptin receptor-deficient mice caused a normalization of blood glucose concentrations, along with a small reduction of body weight (Coppari et al. 2005).
Insulin has also been shown to have similar acute effects to those of leptin when applied to hypothalamic glucose-sensing neurones. Thus, insulin inhibits VMN and ARC GE neurones via activation of KATP channels when applied at elevated (10 mmol l–1) glucose concentrations (Spanswick et al. 2000). However, the effects of insulin on GE neurones may be dependent on local glucose concentrations, since it has also been shown to have no effects on ARC GE neurones at 2.5 mmol l–1 glucose, and activates these neurones at 0.1 mmol l–1 glucose (Wang et al. 2004). In contrast, the effects of insulin on the activity of GI neurones in the hypothalamus are not well characterized. It has recently been shown that the mechanisms by which leptin and insulin activate KATP channels in ARC GE neurones are likely to involve phosphoinositide 3-kinase-dependent actin cytoskeleton reorganization (Mirshamsi et al. 2004).
Neuropeptides involved in controlling feeding also have direct effects on glucose-sensing neurones in the hypothalamus. Both orexins (Muroya et al. 2004) and NPY (Wang et al. 2004) have been shown to inhibit GE neurones, whilst the POMC peptide product, -melanocyte stimulating hormone, activates them (Wang et al. 2004). These interactions may form part of another feedback loop, whereby orexigenic neuropeptides which stimulate feeding, such as NPY and orexin, inhibit GE neurones whose activity would normally signal sufficient energy levels in the body.
Conclusions
The mechanisms through which both GE and GI neurones detect glucose are slowly being elucidated. Recent progress has confirmed the presence of distinct subpopulations of GE and GI neurones, displaying different neuropeptide phenotypes, responses to hormonal stimuli and, in some cases, different glucose-sensing mechanisms. It is possible that these different subpopulations may reflect the range of different physiological functions in which GE and GI neurones are involved. Importantly, these studies have revealed both similarities and striking differences with the regulation by glucose of the ‘corresponding’ islet cells, with a role for AMPK in ß-cells (but not GE neurones), and in both GI neurones and -cells. Further work is required to allow us to fully understand the intracellular mechanisms involved in transducing the signal(s) from glucose to a change in neuronal activity, and to determine how these neurones interact with other neuronal populations and with glia to control satiety and regulate blood glucose concentrations.
References
Ainscow EK, Mirshamsi S, Tang T, Ashford ML & Rutter GA (2002). Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K+ channels. J Physiol 544, 429–445.
Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D & Small CJ (2004). AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279, 12005–12008.
Ashcroft FM, Harrison DE & Ashcroft SJH (1984). Glucose induces closure of single potassium channels in isolated rat pancreatic ß-cells. Nature 312, 446–448.[CrossRef][Medline]
Ashford ML, Boden PR & Treherne JM (1990). Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels. Pflugers Arch 415, 479–483.[CrossRef][Medline]
Burdakov D, Gerasimenko O & Verkhratsky A (2005). Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J Neurosci 25, 2429–2433.
Burdakov D, Jensen LT, Alexopoulos H, Williams RH, Fearon IM, O'Kelly I, Gerasimenko O, Fugger L & Verkhratsky A (2006). Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron 50, 711–722.[CrossRef][Medline]
Chronwall BM, DiMaggio DA, Massari VJ, Pickel VM, Ruggiero DA & O'Donohue TL (1985). The anatomy of neuropeptide-Y-containing neurons in rat brain. Neuroscience 15, 1159–1181.[CrossRef][Medline]
Clark J, Kalra P, Crowley W & Kalra S (1984). Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115, 427–429.[Abstract]
Cohen PC, Zhao X, Cai J, Montez MSC, Rohani P, Feinstein P, Mombaerts & Friedman M (2001). Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 108, 1113–1121.[CrossRef][Medline]
Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, Tang V, Liu SM & Ludwig T (2005). The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metab 1, 63–72.[CrossRef][Medline]
Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD & Low MJ (2001). Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484.[CrossRef][Medline]
Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M & Heiman ML (2003). The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661.[CrossRef][Medline]
da Silva Xavier G, Leclerc I, Salt IP, Doiron B, Hardie DG, Kahn A & Rutter GA (2000). Role of AMP-activated protein kinase in the regulation by glucose of islet ß cell gene expression. Proc Natl Acad Sci U S A 97, 4023–4028.
da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK & Rutter GA (2003). Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 371, 761–774.[CrossRef][Medline]
da Silva Xavier G, Rutter J & Rutter GA (2004). Involvement of Per-Arnt-Sim (PAS) kinase in the stimulation of preproinsulin and pancreatic duodenum homeobox 1 gene expression by glucose. Proc Natl Acad Sci U S A 101, 8319–8324.
Davis JD, Wirtshafter D, Asin KE & Brief D (1981). Sustained intracerebroventricular infusion of brain fuels reduces body weight and food intake in rats. Science 212, 81–83.
Dunn-Meynell AA, Routh VH, Kang L, Gaspers L & Levin BE (2002). Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes 51, 2056–2065.
Edwards C, Abusnana S, Sunter D, Murphy K, Ghatei M & Bloom S (1999). The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol 160, R7–R12.[Abstract]
Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB & Elmquist JK (1999). Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786.[CrossRef][Medline]
Evans ML, McCrimmon RJ, Flanagan DE, Keshavarz T, Fan X, McNay EC, Jacob RJ & Sherwin RS (2004). Hypothalamic ATP-sensitive K+ channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses. Diabetes 53, 2542–2551.
Fioramonti X, Lorsignol A, Taupignon A & Penicaud L (2004). A new ATP-sensitive K+ channel-independent mechanism is involved in glucose-excited neurons of mouse arcuate nucleus. Diabetes 53, 2767–2775.
Funahashi H, Yada T, Muroya S, Takigawa M, Ryushi T, Horie S, Nakai Y & Shioda S (1999). The effect of leptin on feeding-regulating neurons in the rat hypothalamus. Neurosci Lett 264, 117–120.[CrossRef][Medline]
Ganong WF (2000). Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol 27, 422–427.[CrossRef][Medline]
Gromada J, Ma X, Hoy M, Bokvist K, Salehi A, Berggren P-O & Rorsman P (2004). ATP-sensitive K+ channel-dependent regulation of glucagon release and electrical activity by glucose in wild-type and SUR1–/– mouse -cells. Diabetes 53, S181–S189.
Grundy SM, Hansen B, Smith SC Jr, Cleeman JI & Kahn RA (2004). Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 109, 551–556.
Hardie DG, Carling D & Carlson M (1998). The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem 67, 821–855.[CrossRef][Medline]
Ibrahim N, Bosch MA, Smart JL, Qiu J, Rubinstein M, Ronnekleiv OK, Low MJ & Kelly MJ (2003). Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 144, 1331–1340.
Ishihara H, Wang H, Drewes LR & Wollheim CB (1999). Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in ß cells. J Clin Invest 104, 1621–1629.[Medline]
Jobst EE, Enriori PJ & Cowley MA (2004). The electrophysiology of feeding circuits. Trends Endocrinol Metab 15, 488–499.[CrossRef][Medline]
Kang L, Dunn-Meynell AA, Routh VH, Gaspers LD, Nagata Y, Nishimura T, Eiki J, Zhang BB & Levin BE (2006). Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensing. Diabetes 55, 412–420.
Kang L, Routh VH, Kuzhikandathil EV, Gaspers LD & Levin BE (2004). Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53, 549–559.
Kohno D, Gao H-Z, Muroya S, Kikuyama S & Yada T (2003). Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52, 948–956.
Kurata K, Fujimoto K, Sakata T, Etou H & Fukagawa K (1986). D-Glucose suppression of eating after intra-third ventricle infusion in rat. Physiol Behav 37, 615–620.[CrossRef][Medline]
Lam TKT, Gutierrez-Juarez R, Pocai A & Rossetti L (2005). Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943–947.
Levin BE (2002). Metabolic sensors: viewing glucosensing neurons from a broader perspective. Physiol Behav 76, 397–401.[CrossRef][Medline]
Levin BE, Dunn-Meynell AA & Routh VH (1999). Brain glucose sensing and body energy homeostasis: role in obesity and diabetes. Am J Physiol Regul Integr Comp Physiol 276, R1223–R1231.
Liu XH, Morris R, Spiller D, White M & Williams G (2001). Orexin A preferentially excites glucose-sensitive neurons in the lateral hypothalamus of the rat in vitro. Diabetes 50, 2431–2437.
McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ & Sherwin RS (2004). Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53, 1953–1958.
Marx J (2003). Cellular warriors at the battle of the bulge. Science 299, 846–849.
Matschinsky FM, Glaser B & Magnuson M (1998). Pancreatic ß-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 47, 307–315.[Abstract]
Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y, Horiuchi M, Ashcroft F, Minokoshi Y, Roeper J & Seino S (2001). ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4, 507–512.[Medline]
Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ & Kahn BB (2004). AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574.[CrossRef][Medline]
Mirshamsi S, Laidlaw HA, Ning K, Anderson E, Burgess LA, Gray A, Sutherland C & Ashford ML (2004). Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and KATP channel activation. BMC Neurosci 5, 54.[CrossRef][Medline]
Mizuno Y & Oomura Y (1984). Glucose responding neurons in the nucleus tractus solitarius of the rat: in vitro study. Brain Res 307, 109–116.[CrossRef][Medline]
Mobbs CV, Kow LM & Yang XJ (2001). Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses. Am J Physiol Endocrinol Metab 281, E649–E654.
Mountjoy PD, Bailey SJ & Rutter GA (2007). Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity. Diabetologia 50, 168–177.[CrossRef][Medline]
Muroya S, Funahashi H, Yamanaka A, Kohno D, Uramura K, Nambu T, Shibahara M, Kuramochi M, Takigawa M, Yanagisawa M, Sakurai T, Shioda S & Yada T (2004). Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 19, 1524–1534.[CrossRef][Medline]
Muroya S, Uramura K, Sakurai T, Takigawa M & Yada T (2001). Lowering glucose concentrations increases cytosolic Ca2+ in orexin neurons of the rat lateral hypothalamus. Neurosci Lett 309, 165–168.[CrossRef][Medline]
Muroya S, Yada T, Shioda S & Takigawa M (1999). Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neurosci Lett 264, 113–116.[CrossRef][Medline]
Oomura Y, Ono T, Ooyama H & Wayner MJ (1969). Glucose and osmosensitive neurones of the rat hypothalamus. Nature 222, 282–284.[CrossRef][Medline]
Oomura Y, Ooyama H, Sugimori M, Nakamura T & Yamada Y (1974). Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus. Nature 247, 284–286.[CrossRef][Medline]
Panksepp J & Rossi J (1981). D-Glucose infusions into the basal ventromedial hypothalamus and feeding. Behav Brain Res 3, 381–392.[CrossRef][Medline]
Panten U, Christians J, von Kriegstein E, Poser W & Hasselblatt A (1973). Effect of carbohydrates upon fluorescence of reduced pyridine nucleotides from perifused isolated pancreatic islets. Diabetologia 9, 477–482.[CrossRef][Medline]
Ravier MA & Rutter GA (2005). Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic -cells. Diabetes 54, 1789–1797.
Richards SK, Parton LE, Leclerc I, Rutter GA & Smith RM (2005). Over-expression of AMP-activated protein kinase impairs pancreatic ß-cell function in vivo. J Endocrinol 187, 225–235.
Roncero I, Alvarez E, Vazquez P & Blazquez E (2000). Functional glucokinase isoforms are expressed in rat brain. J Neurochem 74, 1848–1857.[CrossRef][Medline]
Rutter GA (2004). Visualising insulin secretion. The Minkowski Lecture 2004. Diabetologia 47, 1861–1872.[CrossRef][Medline]
Rutter GA, da Silva Xavier G & Leclerc I (2003). Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J 375, 1–16.[CrossRef][Medline]
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP & Wilson S (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585.[CrossRef][Medline]
Salt IP, Johnson G, Ashcroft SJ & Hardie DG (1998). AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic ß cells, and may regulate insulin release. Biochem J 335, 533–539.
Sekine N, Cirulli V, Regazzi R, Brown LJ, Gine E, Tamarit-Rodriguez J, Girotti M, Marie S, Macdonald MJ, Wollheim CB & Rutter GA (1994). Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic ß-cells. Potential role in nutrient sensing. J Biol Chem 269, 4895–4902.
Silver IA & Erecinska M (1994). Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. J Neurosci 14, 5068–5076.[Abstract]
Silver IA & Erecinska M (1998). Glucose-induced intracellular ion changes in sugar-sensitive hypothalamic neurons. J Neurophysiol 79, 1733–1745.
Song Z, Levin BE, McArdle JJ, Bakhos N & Routh VH (2001). Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 50, 2673–2681.
Spanswick D, Smith MA, Groppi VE, Logan SD & Ashford ML (1997). Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–525.[CrossRef][Medline]
Spanswick D, Smith MA, Mirshamsi S, Routh VH & Ashford ML (2000). Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3, 757–758.[CrossRef][Medline]
Wang R, Liu X, Hentges ST, Dunn-Meynell AA, Levin BE, Wang W & Routh VH (2004). The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes 53, 1959–1965.
Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K-i, Sugiyama F, Goto K, Yanagisawa N & Sakurai T (2003). Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713.[CrossRef][Medline]
Acknowledgements
We thank the Wellcome Trust (Programme Grant to G.A.R. and Prize studentship to P.D.M.), Juvenile Diabetes Research Foundation, and Medical Research Council for financial support, and Dr Nina Balthasar for discussion.
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