scholarly journals Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose

2009 ◽  
Vol 296 (5) ◽  
pp. E1101-E1109 ◽  
Author(s):  
Victoria E. Cotero ◽  
Vanessa H. Routh
Keyword(s):  
Energy Homeostasis ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Hypothalamic Nucleus ◽  
Compensatory Mechanisms ◽  
Glucose Levels ◽  
Compound C ◽  
Obesity And Diabetes ◽  
Extracellular Glucose ◽  
Pi3k Signaling Pathway

Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose-sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose-sensing neurons. Glucose-sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Our results indicate that insulin opens the KATP channel on VMH GE neurons in 5, 2.5, and 0.1 mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1 mM. This change in the glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (10 nM) but not by the mitogen-activated kinase (MAPK) inhibitor PD-98059 (PD; 50 μM). Finally, neither the AMPK inhibitor compound C nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered.

Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus

2007 ◽  
Vol 292 (4) ◽  
pp. R1418-R1428 ◽  
Author(s):  
Debra D. Canabal ◽  
Zhentao Song ◽  
Joseph G. Potian ◽  
Annie Beuve ◽  
Joseph J. McArdle ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Action Potential ◽  
Insulin Signaling ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
No Production ◽  
Obesity And Diabetes ◽  
Action Potential Frequency ◽  
Extracellular Glucose ◽  
Potential Frequency

Glucose-sensing neurons in the ventromedial hypothalamus (VMH) are involved in the regulation of glucose homeostasis. Glucose-sensing 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-2′,7′-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-β-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.

Brain glucose sensing and body energy homeostasis: role in obesity and diabetes

1999 ◽  
Vol 276 (5) ◽  
pp. R1223-R1231 ◽  
Author(s):  
Barry E. Levin ◽  
Ambrose A. Dunn-Meynell ◽  
Vanessa H. Routh
Keyword(s):  
Firing Rate ◽  
Energy Homeostasis ◽  
Glucose Sensing ◽  
Diabetic Rats ◽  
Brain Glucose ◽  
Physiological Regulation ◽  
Glucose Levels ◽  
Obesity And Diabetes ◽  
Sympathoadrenal Activity ◽  
Insulin Dependent Diabetic

The brain has evolved mechanisms for sensing and regulating glucose metabolism. It receives neural inputs from glucosensors in the periphery but also contains neurons that directly sense changes in glucose levels by using glucose as a signal to alter their firing rate. Glucose-responsive (GR) neurons increase and glucose-sensitive (GS) decrease their firing rate when brain glucose levels rise. GR neurons use an ATP-sensitive K+ channel to regulate their firing. The mechanism regulating GS firing is less certain. Both GR and GS neurons respond to, and participate in, the changes in food intake, sympathoadrenal activity, and energy expenditure produced by extremes of hyper- and hypoglycemia. It is less certain that they respond to the small swings in plasma glucose required for the more physiological regulation of energy homeostasis. Both obesity and diabetes are associated with several alterations in brain glucose sensing. In rats with diet-induced obesity and hyperinsulinemia, GR neurons are hyporesponsive to glucose. Insulin-dependent diabetic rats also have abnormalities of GR neurons and neurotransmitter systems potentially involved in glucose sensing. Thus the challenge for the future is to define the role of brain glucose sensing in the physiological regulation of energy balance and in the pathophysiology of obesity and diabetes.

Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus

2006 ◽  
Vol 291 (5) ◽  
pp. R1283-R1287 ◽  
Author(s):  
Zhentao Song ◽  
Vanessa H. Routh
Keyword(s):  
Insulin Injection ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Saline Control ◽  
Sprague Dawley ◽  
Glucose Levels ◽  
Extracellular Glucose ◽  
Glucose Sensitivity ◽  
Sense And Respond ◽  
Recurrent Hypoglycemia

Recurrent hypoglycemia blunts the brain's ability to sense and respond to subsequent hypoglycemic episodes. Glucose-sensing neurons in the ventromedial hypothalamus nucleus (VMN) are well situated to play a role in hypoglycemia detection. VMN glucose-inhibited (GI) neurons, which decrease their firing rate as extracellular glucose increases, are extremely sensitive to decreased extracellular glucose. We hypothesize that recurrent hypoglycemia decreases the glucose sensitivity of VMN GI neurons. To test our hypothesis, 14- to 21-day-old Sprague-Dawley rats were subcutaneously injected with regular human insulin (4 U/kg) or saline (control) for three consecutive days. Blood glucose levels 1 h after insulin injection on day 3 were significantly lower than on day 1, reflecting an impaired ability to counteract hypoglycemia. On day 4, the glucose sensitivity of VMN GI neurons was measured using conventional whole cell current-clamp recording. After recurrent insulin-induced hypoglycemia, VMN GI neurons only responded to a glucose decrease from 2.5 to 0.1, but not 0.5, mM. Additionally, lactate supplementation also decreased glucose sensitivity of VMN GI neurons. Thus our findings suggest that decreases in glucose sensitivity of VMN GI neurons may contribute to the impairments in central glucose-sensing mechanisms after recurrent hypoglycemia.

scholarly journals New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes

2021 ◽  
Vol 22 (12) ◽  
pp. 6186
Author(s):  
Anna Fosch ◽  
Sebastián Zagmutt ◽  
Núria Casals ◽  
Rosalía Rodríguez-Rodríguez
Keyword(s):  
Glucose Homeostasis ◽  
Energy Homeostasis ◽  
Ventromedial Hypothalamus ◽  
Whole Body ◽  
Metabolic Adaptation ◽  
Glucose Levels ◽  
Obesity And Diabetes ◽  
Hypothalamic Regulation ◽  
Feeding Control ◽  
Body Energy

Despite the substantial role played by the hypothalamus in the regulation of energy balance and glucose homeostasis, the exact mechanisms and neuronal circuits underlying this regulation remain poorly understood. In the last 15 years, investigations using transgenic models, optogenetic, and chemogenetic approaches have revealed that SF1 neurons in the ventromedial hypothalamus are a specific lead in the brain’s ability to sense glucose levels and conduct insulin and leptin signaling in energy expenditure and glucose homeostasis, with minor feeding control. Deletion of hormonal receptors, nutritional sensors, or synaptic receptors in SF1 neurons triggers metabolic alterations mostly appreciated under high-fat feeding, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. Although these studies have provided exciting insight into the implications of hypothalamic SF1 neurons on whole-body energy homeostasis, new questions have arisen from these results. Particularly, the existence of neuronal sub-populations of SF1 neurons and the intricate neurocircuitry linking these neurons with other nuclei and with the periphery. In this review, we address the most relevant studies carried out in SF1 neurons to date, to provide a global view of the central role played by these neurons in the pathogenesis of obesity and diabetes.

Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamus

2007 ◽  
Vol 293 (2) ◽  
pp. R592-R600 ◽  
Author(s):  
Debra D. Canabal ◽  
Joseph G. Potian ◽  
Ricardo G. Duran ◽  
Joseph J. McArdle ◽  
Vanessa H. Routh
Keyword(s):  
Nitric Oxide ◽  
Membrane Potential ◽  
Insulin Signaling ◽  
Mammalian Target Of Rapamycin ◽  
Ventromedial Hypothalamus ◽  
Diabetic Rats ◽  
No Production ◽  
Insulin Regulation ◽  
Obesity And Diabetes ◽  
Extracellular Glucose

Physiological changes in extracellular glucose, insulin, and leptin regulate glucose-excited (GE) and glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH). Nitric oxide (NO) signaling, which is involved in the regulation of food intake and insulin signaling, is altered in obesity and diabetes. We previously showed that glucose and leptin inhibit NO production via the AMP-activated protein kinase (AMPK) pathway, while insulin stimulates NO production via the phosphatidylinositol-3-OH kinase (PI3K) pathway in VMH GI neurons. Hyperglycemia-induced inhibition of AMPK reduces PI3K signaling by activating the mammalian target of rapamycin (mTOR). We hypothesize that hyperglycemia impairs glucose and insulin-regulated NO production in VMH GI neurons. This hypothesis was tested in VMH neurons cultured in hyperglycemic conditions or from streptozotocin-induced type 1 diabetic rats using NO- and membrane potential-sensitive dyes. Neither decreased extracellular glucose from 2.5 to 0.5 mM, nor 5 nM insulin increased NO production in VMH neurons in either experimental condition. Glucose- and insulin-regulated NO production was restored in the presence of the AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside or the mTOR inhibitor rapamycin. Finally, decreased glucose and insulin did not alter membrane potential in VMH neurons cultured in hyperglycemic conditions or from streptozotocin-induced rats. These data suggest that hyperglycemia impairs glucose and insulin regulation of NO production through AMPK inhibition. Furthermore, glucose and insulin signaling pathways interact via the mTOR pathway.

scholarly journals Cellobiose consumption uncouples extracellular glucose sensing and glucose metabolism in Saccharomyces cerevisiae

2016 ◽  
Author(s):  
Kulika Chomvong ◽  
Daniel I. Benjamin ◽  
Daniel K. Nomura ◽  
Jamie H.D. Cate
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcriptional Control ◽  
Energy Homeostasis ◽  
Glucose Sensing ◽  
General Mechanism ◽  
Plasma Membrane Atpase ◽  
Carbon Utilization ◽  
Atp Levels ◽  
Extracellular Glucose ◽  
Starvation Conditions

AbstractGlycolysis is central to energy metabolism in most organisms, and is highly regulated to enable optimal growth. In the yeast Saccharomyces cerevisiae, feedback mechanisms that control flux through glycolysis span transcriptional control to metabolite levels in the cell. Using a cellobiose consumption pathway, we decoupled glucose sensing from carbon utilization, revealing new modular layers of control that induce ATP consumption to drive rapid carbon fermentation. Alterations of the beta subunit of phosphofructokinase (PFK2), H+-plasma membrane ATPase (PMA1), and glucose sensors (SNF3, RGT2) revealed the importance of coupling extracellular glucose sensing to manage ATP levels in the cell. Controlling the upper bound of cellular ATP levels may be a general mechanism used to regulate energy levels in cells, via a regulatory network that can be uncoupled from ATP concentrations under perceived starvation conditions.ImportanceLiving cells are fine-tuned through evolution to thrive in their native environments. Genome alterations to create organisms for specific biotechnological applications may result in unexpected and undesired phenotypes. We used a minimal synthetic biological system in the yeast Saccharomyces cerevisiae as a platform to reveal novel connections between carbon sensing, starvation conditions and energy homeostasis.

Intestinal gluconeogenesis and protein diet: future directions

2020 ◽  
pp. 1-8
Author(s):  
Amandine Gautier-Stein ◽  
Fabienne Rajas ◽  
Gilles Mithieux
Keyword(s):  
Portal Vein ◽  
Energy Homeostasis ◽  
Glucose Sensing ◽  
Endogenous Glucose Production ◽  
Nutrient Sensing ◽  
Whole Body ◽  
Beneficial Effects ◽  
Obesity And Diabetes ◽  
Intestinal Gluconeogenesis ◽  
Protein Diets

High-protein meals and foods are promoted for their beneficial effects on satiety, weight loss and glucose homeostasis. However, the mechanisms involved and the long-term benefits of such diets are still debated. We here review how the characterisation of intestinal gluconeogenesis (IGN) sheds new light on the mechanisms by which protein diets exert their beneficial effects on health. The small intestine is the third organ (in addition to the liver and kidney) contributing to endogenous glucose production via gluconeogenesis. The particularity of glucose produced by the intestine is that it is detected in the portal vein and initiates a nervous signal to the hypothalamic nuclei regulating energy homeostasis. In this context, we demonstrated that protein diets initiate their satiety effects indirectly via IGN and portal glucose sensing. This induction results in the activation of brain areas involved in the regulation of food intake. The μ-opioid-antagonistic properties of protein digests, exerted in the portal vein, are a key link between IGN induction and protein-enriched diet in the control of satiety. From our results, IGN can be proposed as a mandatory link between nutrient sensing and the regulation of whole-body homeostasis. The use of specific mouse models targeting IGN should allow us to identify several metabolic functions that could be controlled by protein diets. This will lead to the characterisation of the mechanisms by which protein diets improve whole-body homeostasis. These data could be the basis of novel nutritional strategies targeting the serious metabolic consequences of both obesity and diabetes.

scholarly journals Effects of Feeding-Related Peptides on Neuronal Oscillation in the Ventromedial Hypothalamus

2019 ◽  
Vol 8 (3) ◽  
pp. 292 ◽  
Author(s):  
Kamon Iigaya ◽  
Yoshino Minoura ◽  
Hiroshi Onimaru ◽  
Sayumi Kotani ◽  
Masahiko Izumizaki
Keyword(s):  
Sympathetic Nerve Activity ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Corticotropin Releasing Factor ◽  
Nerve Activity ◽  
Pituitary Adenylate Cyclase ◽  
Neuronal Oscillation ◽  
Extracellular Glucose ◽  
Frequency Changes ◽  
The Brain

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior, obesity, and thermoregulation. The VMH contains glucose-sensing neurons, the firing of which depends on the level of extracellular glucose and which are involved in maintaining the blood glucose level via the sympathetic nervous system. The VMH also expresses various receptors of the peptides related to feeding. However, it is not well-understood whether the action of feeding-related peptides mediates the activity of glucose-sensing neurons in the VMH. In the present study, we examined the effects of feeding-related peptides on the burst-generating property of the VMH. Superfusion with insulin, pituitary adenylate cyclase-activating polypeptide, corticotropin-releasing factor, and orexin increased the frequency of the VMH oscillation. In contrast, superfusion with leptin, cholecystokinin, cocaine- and amphetamine-regulated transcript, galanin, ghrelin, and neuropeptide Y decreased the frequency of the oscillation. Our findings indicated that the frequency changes of VMH oscillation in response to the application of feeding-related peptides showed a tendency similar to changes of sympathetic nerve activity in response to the application of these substances to the brain.

scholarly journals Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose

2009 ◽  
Vol 296 (4) ◽  
pp. C746-C756 ◽  
Author(s):  
Beth Ann Murphy ◽  
Xavier Fioramonti ◽  
Nina Jochnowitz ◽  
Kurt Fakira ◽  
Karen Gagen ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Neuropeptide Y ◽  
Energy Homeostasis ◽  
Neuronal Excitability ◽  
Glucose Sensing ◽  
Extracellular Glucose ◽  
Glucose Fluctuations ◽  
Induced Changes ◽  
Amp Activated Protein Kinase

Fasting increases neuropeptide Y (NPY) expression, peptide levels, and the excitability of NPY-expressing neurons in the hypothalamic arcuate (ARC) nucleus. A subpopulation of ARC-NPY neurons (∼40%) are glucose-inhibited (GI)-type glucose-sensing neurons. Hence, they depolarize in response to decreased glucose. Because fasting enhances NPY neurotransmission, we propose that during fasting, GI neurons depolarize in response to smaller decreases in glucose. This increased excitation in response to glucose decreases would increase NPY-GI neuronal excitability and enhance NPY neurotransmission. Using an in vitro hypothalamic explant system, we show that fasting enhances NPY release in response to decreased glucose concentration. By measuring relative changes in membrane potential using a membrane potential-sensitive dye, we demonstrate that during fasting, a smaller decrease in glucose depolarizes NPY-GI neurons. Furthermore, incubation in low (0.7 mM) glucose enhanced while leptin (10 nM) blocked depolarization of GI neurons in response to decreased glucose. Fasting, leptin, and glucose-induced changes in NPY-GI neuron glucose sensing were mediated by 5′-AMP-activated protein kinase (AMPK). We conclude that during energy sufficiency, leptin reduces the ability of NPY-GI neurons to sense decreased glucose. However, after a fast, decreased leptin and glucose activate AMPK in NPY-GI neurons. As a result, NPY-GI neurons become depolarized in response to smaller glucose fluctuations. Increased excitation of NPY-GI neurons enhances NPY release. NPY, in turn, shifts energy homeostasis toward increased food intake and decreased energy expenditure to restore energy balance.

scholarly journals Glycemic state regulates melanocortin, but not nesfatin-1, responsiveness of glucose-sensing neurons in the nucleus of the solitary tract

2015 ◽  
Vol 308 (8) ◽  
pp. R690-R699 ◽  
Author(s):  
Andrea Mimee ◽  
Alastair V. Ferguson
Keyword(s):  
Membrane Potential ◽  
Energy Homeostasis ◽  
Glucose Sensing ◽  
Solitary Tract ◽  
Multiple Sources ◽  
Electrophysiological Studies ◽  
Extracellular Glucose ◽  
Recording Conditions ◽  
Cell Current ◽  
Anorexigenic Peptide

The nucleus of the solitary tract (NTS) is a medullary integrative center with critical roles in the coordinated control of energy homeostasis. Here, we used whole cell current-clamp recordings on rat NTS neurons in slice preparation to identify the presence of physiologically relevant glucose-sensing neurons. The majority of NTS neurons ( n = 81) were found to be glucose-responsive, with 35% exhibiting a glucose-excited (GE) phenotype (mean absolute change in membrane potential: 9.5 ± 1.1 mV), and 21% exhibiting a glucose-inhibited (GI) response (mean: 6.3 ± 0.7 mV). Furthermore, we found glucose-responsive cells are preferentially influenced by the anorexigenic peptide α-melanocyte-stimulating hormone (α-MSH), but not nesfatin-1. Accordingly, alterations in glycemic state have profound effects on the responsiveness of NTS neurons to α-MSH, but not to nesfatin-1. Indeed, NTS neurons showed increasing responsiveness to α-MSH as extracellular glucose concentrations were decreased, and in hypoglycemic conditions, all NTS neurons were depolarized by α-MSH (mean 10.6 ± 3.2 mV; n = 8). Finally, decreasing levels of extracellular glucose correlated with a significant hyperpolarization of the baseline membrane potential of NTS neurons, highlighting the modulatory effect of glucose on the baseline excitability of cells in this region. Our findings reveal individual NTS cells are capable of integrating multiple sources of metabolically relevant inputs, highlight the rapid capacity for plasticity in medullary melanocortin circuits, and emphasize the critical importance of physiological recording conditions for electrophysiological studies pertaining to the central control of energy homeostasis.

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