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Synaptic Glutamate Release by Ventromedial Hypothalamic Neurons Is Part of the Neurocircuitry that Prevents Hypoglycemia
Open accessAbstract
The importance of neuropeptides in the hypothalamus has been experimentally established. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia.
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“Tong et al. (2007) recently demonstrated a critical role for the vesicular glutamate transporter (VGLUT2) in counterregulatory action against insulin-induced hypoglycemia specifically in SF-1 neurons of the VMH.”
BackgroundA Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance
Martins, L., Seoane-Collazo, P., Contreras, C., González-García, I., Martínez-Sánchez, N., González, F., Zalvide, J., Gallego, R., Diéguez, C., Nogueiras, R., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.045 · Cited by 154
“It is known that glutamate and glutamate transporters, particularity glutamate vesicular transporter 2 (VGLUT2), play a main role in hypothalamic regulation of energy balance (Tong et al., 2007).”
Wired on sugar: the role of the CNS in the regulation of glucose homeostasis
Grayson, B. E., Seeley, R. J., & Sandoval, D. A. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3409 · Cited by 125
Central insulin and leptin-mediated autonomic control of glucose homeostasis
Marino, J. S., Xu, Y., & Hill, J. W. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.03.001 · Cited by 129
Obesity – A neuropsychological disease? Systematic review and neuropsychological model
Jauch‐Chara, K., & Oltmanns, K. M. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.12.001 · Cited by 136
Martínez‐Sánchez, N., Sweeney, O., Sidarta-Oliveira, D., Caron, A., Stanley, S. A., & Domingos, A. I. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.017 · Cited by 127
“In keeping with a role for VMH neurons, knockout of glutamate transporter, VGLUT2, in steroidogenic factor-1 (SF1) neurons (a major subset of VMH neurons) impairs the pancreatic glucagon response to fasting leading to hypoglycemia (Tong et al., 2007).”
Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators
Sánchez-Lasheras, C., Könner, A. C., & Brüning, J. C. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.08.002 · Cited by 127
“counter-regulatory response to hypoglycemia [190].”
Circadian Control of the Daily Plasma Glucose Rhythm: An Interplay of GABA and Glutamate
Kalsbeek, A., Foppen, E., Schalij, I., Heijningen, C. L. V., van der Vliet, J., Fliers, E., & Buijs, R. M. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003194 · Cited by 120
“More recently Tong et al [47] very nicely demonstrated that glutamate release from VMH neurons is necessary to prevent hypoglycemia (i.”
BackgroundVGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation
Birgner, C., Nordenankar, K., Lundblad, M., Méndez, J. A. T., Smith, C., Grevès, M. L., Galter, D., Olson, L., Fredriksson, A., Trudeau, L., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910986107 · Cited by 119
“VGLUT2 also has been shown to play a role in the hypothalamic neurocircuitry that prevents hypoglycemia (11).”
BackgroundMedullary Circuitry Regulating Rapid Eye Movement Sleep and Motor Atonia
Vetrivelan, R., Fuller, P. M., Tong, Q., & Lu, J. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0737-09.2009 · Cited by 118
“For experiment 3, we used two different transgenic mouse models (25–35 g), which had lox P sites flanking exon 2 of either the vesicular glutamate transporter 2 (Vglut2) gene or the vesicular GABA transporter (Vgat) gene (Tong et al., 2007, 2008).”
BackgroundMethodVujović, N., Gooley, J. J., Jhou, T. C., & Saper, C. B. (2015) · The Journal of Comparative Neurology · doi:10.1002/cne.23812 · Cited by 118
“These dorsomedial The Journal of Comparative Neurology | Research in Systems Neuroscience 2733 VMH neurons are implicated in energy homeostasis and maintenance of plasma glucose levels (Tong et al., 2007; Hawke et al., 2009; Xu et al., 2010).”
BackgroundThe selfish brain: Competition for energy resources
Peters, A. (2010) · American Journal of Human Biology · doi:10.1002/ajhb.21106 · Cited by 121
Hypothalamic leptin regulation of energy homeostasis and glucose metabolism
Morton, G. J. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.135590 · Cited by 114
“…neurons (Song & Routh, 2005; Kang et al. 2006) that are essential for autonomic and hormonal responses to hypoglycaemia (McCrimmon et al. 2005; Tong et al. 2007) and this glucose-sensing function is dependent on KATP channel activation (McCrimmon et al. 2005), similar to the effects of both…”
BackgroundFunctions for pro-opiomelanocortin-derived peptides in obesity and diabetes
Mountjoy, K. G. (2010) · Biochemical Journal · doi:10.1042/bj20091957 · Cited by 110
PACAP Neurons in the Hypothalamic Ventromedial Nucleus Are Targets of Central Leptin Signaling
Hawke, Z., Ivanov, T. R., Bechtold, D. A., Dhillon, H., Lowell, B. B., & Luckman, S. M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1526-09.2009 · Cited by 109
“This is in stark contrast to other hypothalamic nuclei, such as the Arc, PVN, and LH. VMN cells are predominantly glutamatergic, and Tong et al. (2007) demonstrated that blocking glutamate release from SF-1-positive cells by deletion of the glutamate vesicular transporter, VGLUT2, does not produce…”
BackgroundResultBrain expression of Cre recombinase driven by pancreas‐specific promoters
Song, J., Xu, Y., Hu, X., Choi, B. J., & Tong, Q. (2010) · genesis · doi:10.1002/dvg.20672 · Cited by 107
“SF1-Cre is known to specifically express Cre in VMH neurons (Tong et al., 2007).”
BackgroundMultiple hypothalamic circuits sense and regulate glucose levels
Karnani, M., & Burdakov, D. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00527.2010 · Cited by 107
“Recent data show that most VMH neurons express a protein called steroidogenic factor-1 (SF-1) and that SF-1-expressing neurons have key roles in glucose homeostasis (103, 114).”
BackgroundHow the selfish brain organizes its supply and demand
Hitze, B. (2010) · Frontiers in Neuroenergetics · doi:10.3389/fnene.2010.00007 · Cited by 105
“Besides, K ATP channels located on GABAergic neurons in the VMH are able to sense small and early changes in cerebral ATP concentrations and thereby disinhibiting VMH glutamatergic mechanisms and in so doing stimulate the SNS/HPA system (Chan et al., 1991; Tong et al., 2007).”
Glutamate Mediates the Function of Melanocortin Receptor 4 on Sim1 Neurons in Body Weight Regulation
Xu, Y., Wu, Z., Sun, H., Zhu, Y., Kim, E. R., Lowell, B. B., Arenkiel, B. R., Xu, Y., & Tong, Q. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.003 · Cited by 105
“MC4R-Bearing Sim1 Neurons Are Glutamatergic Vesicular glutamate transporter 2 (Vglut2, also known as Slc17a6), a gene expressed in glutamatergic neurons for loading glutamate in vesicles for presynaptic release, is abundant in the hypothalamus (Fremeau et al., 2004; Tong et al., 2007).”
BackgroundGABAergic Restriction of Network Dynamics Regulates Interneuron Survival in the Developing Cortex
Duan, Z. R. S., Che, A., Chu, P., Modol, L., Bollmann, Y., Babij, R., Fetcho, R. N., Otsuka, T., Fuccillo, M. V., Liston, C., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.10.008 · Cited by 102
“To achieve a significant reduction in GABAergic tone, we crossed the Lhx6Cre line to vesicular GABA transporter floxed mice (VGATfl/fl) (Tong et al. 2007) (Figure S1A–S1R).”
MethodDiggs‐Andrews, K. A., Zhang, X., Song, Z., Daphna-Iken, D., Routh, V. H., & Fisher, S. J. (2010) · Diabetes · doi:10.2337/db10-0401 · Cited by 101
“In several studies, 2 -DG has been used as a hypoglycemia surrogate in rat and mouse models of impaired counter regulation (58;75;135-139).”
BackgroundMethodInfluentialHypothalamic Control of Systemic Glucose Homeostasis: The Pancreas Connection
Pozo, M., & Claret, M. (2018) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.05.001 · Cited by 97
“Notably, the counterregulatory response to insulin-induced hypoglycemia and central glucopenia is impaired in mutant mice [60].”
BackgroundRespiratory‐related outputs of glutamatergic, hypercapnia‐responsive parabrachial neurons in mice
Yokota, S., Kaur, S., VanderHorst, V., Saper, C. B., & Chamberlin, N. L. (2014) · The Journal of Comparative Neurology · doi:10.1002/cne.23720 · Cited by 97
“Free-floating sections were incubated overnight with hybridization buffer containing probes for vGluT2 [1 mg/ ml; template graciously donated by Dr. Qinchung Tong (Tong et al., 2007)] or fragmented probes by alkaline hydrolysis for GAD67, 0.5 mg/ml, full-length cDNA encoding rat GAD67 (3.2 kb; Erlander et al., 1991) f…”
MethodInfluentialDicken, M. S., Tooker, R. E., & Hentges, S. T. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6032-11.2012 · Cited by 93
“For example, glutamate release from neurons in the ventromedial hypothalamus is an important step in preventing hypoglycemia (Tong et al., 2007), the release of GABA from NPY/AGRP neurons in the ARC is also required for the normal regulation of energy balance (Tong et al., 2008), and GABA release…”
BackgroundAmo, R., Matias, S., Yamanaka, A., Tanaka, K. F., Uchida, N., & Watabe‐Uchida, M. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01109-2 · Cited by 94
Influence of Insulin in the Ventromedial Hypothalamus on Pancreatic Glucagon Secretion In Vivo
Paranjape, S., Chan, O. T. M., Zhu, W., Horblitt, A. M., McNay, E. C., Cresswell, J. A., Bogan, J. S., McCrimmon, R. J., & Sherwin, R. S. (2010) · Diabetes · doi:10.2337/db10-0014 · Cited by 98
“Moreover, mice with selective loss of glutamate release in steroidogenic factor 1 neurons, which are expressed exclusively in the VMH, show a markedly impaired glucagon secretory response to acute hypoglycemia (11).”
BackgroundCoutinho, E. A., Okamoto, S., Ishikawa, A. W., Yokota, S., Wada, N., Hirabayashi, T., Saito, K., Sato, T., Takagi, K., Wang, C.-C., et al. (2017) · Diabetes · doi:10.2337/db16-1344 · Cited by 96
Ghrelin and lipid metabolism: key partners in energy balance
Varela, L., Vazquez, M. J., Cordido, F., Nogueiras, R., Vidal‐Puig, A., Diéguez, C., & López, M. (2010) · Journal of Molecular Endocrinology · doi:10.1677/jme-10-0068 · Cited by 95
“The VMH integrates peripheral signals alongside other hypothalamic nuclei and the brainstem, connected through specific neuronal projections (Tong et al. 2007).”
Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT
Aguilar, J. I., Dunn, M., Mingote, S., Karam, C. S., Farino, Z. J., Sonders, M. S., Choi, S. J., Grygoruk, A., Zhang, Y., Cela, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.038 · Cited by 89
“…was selectively disrupted in VTA neurons and their NAc projections via injection of AAV-driven mCherry-labeled Cre recombinase (AAV-DJ EF1amCherry-cre) in the VTA of adult VGLUT2flox/flox mice (Tong et al., 2007); AAV-drivenmCherry alone (AAV-DJ-EF1a-mCherry) served as a control (Figure 7C).”
Hypothalamic glucose-sensing mechanisms
Yoon, N. A., & Diano, S. (2021) · Diabetologia · doi:10.1007/s00125-021-05395-6 · Cited by 105
“In turn, AMPK causes neuronal depolarisation, increased frequency of action potential and neurotransmitter release, including release of glutamate, which leads to the activation of CRRs to hypoglycaemia [26].”
BackgroundInfluence of VMH fuel sensing on hypoglycemic responses
Chan, O. T. M., & Sherwin, R. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.08.005 · Cited by 87
AMPK and the neuroendocrine regulation of appetite and energy expenditure
Stark, R., Ashley, S. E., & Andrews, Z. B. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.012 · Cited by 94
“Indeed, deleting glutamate synaptic transmission from VMH neurons, increased long-term food intake and susceptibility to diet-induced obesity (Tong et al., 2007).”
Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance
He, Y., Xu, P., Wang, C., Xia, Y., Yu, M., Yang, Y., Yu, K., Cai, X., Qu, N., Saito, K., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15982-7 · Cited by 84
Tennese, A. A., & Wevrick, R. (2011) · Endocrinology · doi:10.1210/en.2010-0709 · Cited by 87
Cheung, C. C., Kurrasch, D. M., Liang, J. K., & Ingraham, H. A. (2012) · The Journal of Comparative Neurology · doi:10.1002/cne.23226 · Cited by 90
“…of the hypothalamus (VMH) is known to regulate many physiological processes, including reproduction, defensive responses, locomotor activity, glucose homeostasis, and appetite control (Canteras, 2002; King, 2006; Kow and Pfaff, 1998; Tong et al., 2007; Yokawa et al., 1989; Zhao et al., 2008).”
BackgroundResultInfluentialBrain glucose sensing in homeostatic and hedonic regulation
Steinbusch, L. K. M., Labouèbe, G., & Thorens, B. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.06.005 · Cited by 95
The Role of AMPK Signaling in Brown Adipose Tissue Activation
van der Vaart, J. I., Boon, M. R., & Houtkooper, R. H. (2021) · Cells · doi:10.3390/cells10051122 · Cited by 90
Metadata
- Authors
- Tong, Q., Ye, C., McCrimmon, R. J., Dhillon, H., Choi, B., Kramer, M. D., Yu, J., Yang, Z., Christiansen, L. M., Lee, C. E., Choi, C. S., Zigman, J. M., Shulman, G. I., Sherwin, R. S., Elmquist, J. K., & Lowell, B. B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Yale University (US)
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lowell, Bradford B.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2007-05
- Volume
- 5
- Issue
- 5
- Pages
- 383-393
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC1934926
- OpenAlex
- W1995998852
- Cited by
- 413
- References
- 62
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 32 · 2023: 23 · 2022: 23 · 2021: 30 · 2020: 22 · 2019: 10 · 2018: 25 · 2017: 27 · 2016: 16 · 2015: 19 · 2014: 20 · 2013: 26 · 2012: 27
- FWCI
- 7.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- American Diabetes Association Research Foundation
- Richard and Susan Smith Family Foundation
- Boston Area Diabetes Endocrinology Research Center
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, P01DK56116, R01DK071051, P01DK056116, P30DK046200, R01DK040936, R01DK071320, U24DK059635, DK071320, R01DK069831, R01DK072409, R37DK020495)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- ventromedial hypothalamus, glutamate release, VGLUT2, glucagon, hypoglycemia, insulin-induced hypoglycemia, PGC-1α, gluconeogenesis, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, 2-deoxyglucose, hypothalamic neurons, glucose homeostasis
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Electrophysiology, Glucagon, Glucose-6-Phosphatase, Hypoglycemia, Hypothalamus, Insulin, Liver, Mice, Transgenic, Neurons, Synapses, Transcription Factors, Trans-Activators, In Situ Hybridization, Glutamic Acid, Vesicular Glutamate Transport Protein 2, Mice
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