Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) were studied using visually guided slicepatch recording techniques in brain slices from 14-to 21-day-old male Sprague-Dawley rats. Whole-cell current-clamp recordings were made as extracellular glucose levels were increased (from 2.5 to 5 or 10 mmol/l) or decreased (from 2.5 to 0.1 mmol/l). Using these physiological conditions to define glucosensing neurons, two subtypes of VMN glucosensing neurons were directly responsive to alterations in extracellular glucose levels. Another three subtypes were not directly glucose-sensing themselves, but rather were presynaptically modulated by changes in extracellular glucose. Of the VMN neurons, 14% were directly inhibited by decreases in extracellular glucose (glucose-excited [GE]), and 3% were directly excited by decreases in extracellular glucose (glucose-inhibited [GI]). An additional 14% were presynaptically excited by decreased glucose (PED neurons). The other two subtypes of glucosensing neurons were either presynaptically inhibited (PIR; 11%) or excited (PER; 8%) when extracellular glucose was raised to >2.5 mmol/l. GE neurons sensed decreased glucose via an ATP-sensitive K ؉ (K ATP ) channel. The inhibitory effect of increased glucose on PIR neurons appears to be mediated by a presynaptic ␥-aminobutyric acid-ergic glucosensing neuron that probably originates outside the VMN. Finally, all types of glucosensing neurons were both fewer in number and showed abnormal responses to glucose in a rodent model of diet-induced obesity and type 2 diabetes.
Glucose directly alters the action potential frequency of glucosensing neurons in the ventromedial hypothalamic nucleus (VMN). Glucose-excited neurons increase, and glucose-inhibited neurons decrease, their action potential frequency as glucose increases from 0.1 to 2.5 mmol/l. Glucose-excited neurons utilize the ATP-sensitive K ؉ channel (K ATP channel) to sense glucose, whereas glucose opens a chloride channel in glucoseinhibited neurons. We tested the hypothesis that lactate, an alternate energy substrate, also regulates the action potential frequency of VMN glucose-excited and -inhibited but not nonglucosensing neurons. As expected, lactate reversed the inhibitory effects of decreased glucose on VMN glucose-excited neurons via closure of the K ATP channel. Although increasing glucose from 2.5 to 5 mmol/l did not affect the activity of glucose-excited neurons, the addition of 0.5 mmol/l lactate or the K ATP channel blocker tolbutamide increased their action potential frequency. In contrast to the glucose-excited neurons, lactate did not reverse the effects of decreased glucose on VMN glucose-inhibited neurons. In fact, it increased their action potential frequency in both low and 2.5 mmol/l glucose. This effect was mediated by both K ATP and chloride channels. Nonglucosensing neurons were not affected by lactate. Thus, glucose and lactate have similar effects on VMN glucose-excited neurons, but they have opposing effects on VMN glucose-inhibited neurons. Diabetes 54:15-22, 2005 T he ventromedial hypothalamic nucleus (VMN) plays an important role in the central regulation of glucose homeostasis (1). Electrical stimulation of the ventromedial hypothalamus (VMH), which contains the VMN, activates the sympathoadrenal system in a manner similar to that seen during initiation of the counterregulatory response to hypoglycemia (2). Moreover, local VMH glucopenia caused by delivery of the nonmetabolizable glucose analog 2-deoxyglucose into the VMH causes the release of counterregulatory hormones (3). In contrast, glucose infusion into the VMH suppresses their release during systemic hypoglycemia (4). We have described five subtypes of VMN glucosensing neurons that alter their action potential frequency in response to physiological changes in extracellular glucose from 2.5 to 0.1 or 5 mmol/l (5). Of these VMN glucosensing neurons, two subtypes are directly sensitive to decreases in extracellular glucose levels; glucose-excited neurons increase whereas glucose-inhibited neurons decrease their action potential frequency as extracellular glucose increases from 0.1 to 2.5 mmol/l (5). Like pancreatic -cells, about half of both VMN glucose-excited and -inhibited neurons appear to utilize a special hexokinase known as glucokinase to sense glucose (6). The actual response to glucose is mediated by the ATP-sensitive K ϩ (K ATP channel) and a Cl Ϫ channel for glucose-excited and -inhibited neurons, respectively (5).Lactate may be an alternate energy source in the brain (7-9). Both neurons and astrocytes produce lactate (7). In ...
Four types of responses to glucose changes have been described in the arcuate nucleus (ARC): excitation or inhibition by low glucose concentrations <5 mmol/l (glucose-excited and -inhibited neurons) and by high glucose concentrations >5 mmol/l (high glucose-excited and -inhibited neurons). However, the ability of the same ARC neuron to detect low and high glucose concentrations has never been investigated. Moreover, the mechanism involved in mediating glucose sensitivity in glucose-inhibited neurons and the neurotransmitter identity (neuropeptide Y [
Murphy BA, Fakira KA, Song Z, Beuve A, Routh VH. AMPactivated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am J Physiol Cell Physiol 297: C750 -C758, 2009. First published July 1, 2009; doi:10.1152/ajpcell.00127.2009The mechanisms by which glucose regulates the activity of glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH) are largely unknown. We have previously shown that AMP-activated protein kinase (AMPK) increases nitric oxide (NO) production in VMH GI neurons. We hypothesized that AMPK-mediated NO signaling is required for depolarization of VMH GI neurons in response to decreased glucose. In support of our hypothesis, inhibition of neuronal nitric oxide synthase (nNOS) or the NO receptor soluble guanylyl cyclase (sGC) blocked depolarization of GI neurons to decreased glucose from 2.5 to 0.7 mM or to AMPK activation. Conversely, activation of sGC or the cell-permeable analog of cGMP, 8-bromoguanosine 3Ј,5Ј-cyclic monophosphate (8-Br-cGMP), enhanced the response of GI neurons to decreased glucose, suggesting that stimulation of NO-sGC-cGMP signaling by AMPK is required for glucose sensing in GI neurons. Interestingly, the AMPK inhibitor compound C completely blocked the effect of sGC activation or 8-Br-cGMP, and 8-Br-cGMP increased VMH AMPK␣2 phosphorylation. These data suggest that NO, in turn, amplifies AMPK activation in GI neurons. Finally, inhibition of the cystic fibrosis transmembrane regulator (CFTR) Cl Ϫ conductance blocked depolarization of GI neurons to decreased glucose or AMPK activation, whereas decreased glucose, AMPK activation, and 8-BrcGMP increased VMH CFTR phosphorylation. We conclude that decreased glucose triggers the following sequence of events leading to depolarization in VMH GI neurons: AMPK activation, nNOS phosphorylation, NO production, and stimulation of sGC-cGMP signaling, which amplifies AMPK activation and leads to closure of the CFTR. soluble guanylyl cyclase; guanosine 3Ј,5Ј-cyclic monophosphate; cystic fibrosis transmembrane regulator; glucose-sensing neurons; membrane potential sensitive dye THE VENTROMEDIAL HYPOTHALAMUS (VMH), which contains the arcuate and ventromedial (VMN) nuclei, is critical for regulating energy and glucose homeostasis (22). Within the VMH, specialized glucose-sensing neurons change their electrical activity in response to changes in extracellular glucose concentration (16,24,28). Glucose-excited (GE) neurons increase, whereas glucose-inhibited (GI) neurons decrease, their action potential frequency as glucose levels rise (23). Like the pancreatic -cell, the ATP-sensitive K ϩ channel mediates glucose sensing in VMH GE neurons (23,28). Less is known about the ion channel involved in glucose sensing by GI neurons; however, our previous data suggest that glucose inhibits VMH GI neurons via the activation of the cystic fibrosis transmembrane regulator (CFTR) Cl Ϫ conductance (9, 23). The cellular fuel sensor 5Ј-AMP-activated protein kinase (AMPK) confers gluc...
Canabal DD, Song Z, Potian JG, Beuve A, McArdle JJ, Routh VH. Glucose, insulin and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol 292: R1418 -R1428, 2007. First published December 24, 2006; doi:10.1152/ajpregu.00216.2006.-Glucose-sensing neurons in the ventromedial hypothalamus (VMH) are involved in the regulation of glucose homeostasis. Glucosesensing neurons alter their action potential frequency in response to physiological changes in extracellular glucose, insulin, and leptin. Glucose-excited neurons decrease, whereas glucose-inhibited (GI) neurons increase, their action potential frequency when extracellular glucose is reduced. Central nitric oxide (NO) synthesis is regulated by changes in local fuel availability, as well as insulin and leptin. NO is involved in the regulation of food intake and is altered in obesity and diabetes. Thus this study tests the hypothesis that NO synthesis is a site of convergence for glucose, leptin, and insulin signaling in VMH glucose-sensing neurons. With the use of the NO-sensitive dye 4-amino-5-methylamino-2Ј,7Ј-difluorofluorescein in conjunction with the membrane potential-sensitive dye fluorometric imaging plate reader, we found that glucose and leptin suppress, whereas insulin stimulates neuronal nitric oxide synthase (nNOS)-dependent NO production in cultured VMH GI neurons. The effects of glucose and leptin were mediated by suppression of AMP-activated protein kinase (AMPK). The AMPK activator 5-aminoimidazole-4-carboxamide-1--4-ribofuranoside (AICAR) increased both NO production and neuronal activity in GI neurons. In contrast, the effects of insulin on NO production were blocked by the phosphoinositide 3-kinase inhibitors wortmannin and LY-294002. Furthermore, decreased glucose, insulin, and AICAR increase the phosphorylation of VMH nNOS, whereas leptin decreases it. Finally, VMH neurons express soluble guanylyl cyclase, a downstream mediator of NO signaling. Thus NO may mediate, in part, glucose, leptin, and insulin signaling in VMH glucose-sensing neurons. ventromedial hypothalamus; glucose-sensing neurons; leptin; insulin; nitric oxide; adenosine 5Ј-monophosphate-activated protein kinase THE VENTROMEDIAL HYPOTHALAMUS (VMH), which contains the ventromedial (VMN) and arcuate (ARC) nuclei, is critical for the regulation of glucose and energy homeostasis (34). This region contains specialized neurons whose activity is regulated by physiologically relevant changes in extracellular glucose (36,37,42). Glucose-excited (GE) neurons decrease, whereas glucose-inhibited (GI) neurons increase, their action potential frequency (APF) when extracellular glucose is reduced (36). GE neurons activate ATP-sensitive K ϩ (K ATP ) channels in response to decreased glucose. GI neurons appear to close an ATP-activated Cl Ϫ channel, although the identity of this channel is unknown (36). Glucose-sensing neurons also possess insulin and leptin receptors (22,39,40,42). Thus gluc...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.