Hypothalamic glucose sensing: Making ends meet

Frontiers in Systems Neuroscience

Volumn 8, Issue DEC, 2014, Pages

  Routh, Vanessa H ^a   Hao, Lihong ^a,b   Santiago, Ammy M ^a,b   Sheng, Zhenyu ^a   Zhou, Chunxue ^a,b  

^a RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

^b RUTGERS UNIVERSITY   (United States)

Author keywords

Agouti related peptide; Glucose homeostasis; Glucose excited neurons; Glucose inhibited neurons; Hypoglycemia; Nitric oxide; Orexin; Starvation

Indexed keywords

4 AMINOBUTYRIC ACID; ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; GHRELIN; GLUCOSE; GLUCOSE TRANSPORTER 2; GLUCOSE TRANSPORTER 4; INSULIN RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN; NEUROPEPTIDE Y; OREXIN; SODIUM GLUCOSE COTRANSPORTER 2;

ARCUATE NUCLEUS; BIOLOGICAL PHENOMENA AND FUNCTIONS CONCERNING THE ENTIRE ORGANISM; DIET RESTRICTION; DORSOMEDIAL HYPOTHALAMIC NUCLEUS; ENZYME ACTIVITY; GLIA CELL; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; GLUCOSE SENSING; GLUCOSE SENSOR; GLUCOSE TRANSPORT; HOMEOSTASIS; HYPOGLYCEMIA; HYPOTHALAMUS; HYPOTHALAMUS VENTROMEDIAL NUCLEUS; INSULIN SENSITIVITY; MICROGLIA; NEUROENDOCRINE SYSTEM; NONHUMAN; PHENOTYPE; REGULATORY MECHANISM; REVIEW;

EID: 84917741721     PISSN: 16625137     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnsys.2014.00236     Document Type: Review

References (156)

1. Ackroff, K., Yiin, Y.-M., and Sclafani, A. (2010). Post-oral infusion sites that support glucose-conditioned flavor preferences in rats. Physiol. Behav. 99, 402-411. doi: 10.1016/j.physbeh.2009.12.012
2. Adachi, A., Shimizu, N., Oomura, Y., and Kobashi, M. (1984). Convergence of heptoportal glucose-sensitive afferent signals to glucose-sensitive units within the nucleus of the solitary tract. Neurosci. Lett. 46, 215-218. doi: 10.1016/0304-3940(84)90444-0
3. Ahima, R. S., Saper, C. B., Flier, J. S., and Elmquist, J. K. (2000). Leptin regulation of neuroendocrine systems.Front. Neuroendocrinol. 21:197. doi: 10.1006/frne.2000.0197
4. Alvarez-Buylla, R., and de Alvarez-Buylla, E. R. (1998). Carotid sinus receptors participate in glucose homeostasis.Respir. Physiol. 72, 347-360. doi: 10.1016/0034-5687(88)90093-X
5. Anand, B. K., China, G. S., Sharma, K. N., Dua, S., and Singh, B. (1964). Activity of single neurons in the hypothalamus feeding centers: effect of glucose. Am. J. Physiol. 2207, 1146-1154.
6. Antunes, V. R., Brailoiu, G. C., Kwok, E. H., Scruggs, P., and Dun, N. J. (2001). Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1801-R1807.
7. + channels. Pfugers Arch. 415, 479-483.
8. + channels. Br. J. Pharmacol. 101, 531-540. doi: 10.1111/j.1476-5381.1990.tb14116.x
9. Bady, I., Marty, N., Dallaporta, M., Emery, M., Gyger, J., Tarussio, D., et al. (2006). Evidence from Glut2-Null mice that glucose is a critical physiological regulator of feeding. Diabetes 55, 988-995. doi: 10.2337/diabetes.55.04.06.db05-1386
10. Balfour, R. H., Hansen, A. M. K., and Trapp, S. (2006). Neuronal responses to transient hypoglycaemia in the dorsal vagal complex of the rat brainstem. J. Physiol. 570, 469-484. doi: 10.1113/jphysiol.2005.098822
11. Baver, S. B., Hope, K., Guyot, S., Bjørbaek, C., Kaczorowski, C., and O'Connell, K. M. S. (2014). Leptin Modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J. Neurosci. 34, 5486-5496. doi: 10.1523/JNEUROSCI.4861-12.2014
12. Beall, C., Hamilton, D., Gallagher, J., Logie, L., Wright, K., Soutar, M., et al. (2012). Mouse hypothalamic GT1-7 cells demonstrate AMPK-dependent intrinsic glucose-sensing behaviour. Diabetologia 55, 2432-2444. doi: 10.1007/s00125-012-2617-y.
13. Beck, B. (2000). Neuropeptides and obesity. [Review] [170 refs]. Nutrition 16, 916-923. doi: 10.1016/S0899-9007(00)00410-X
14. Becskei, C., Lutz, T. A., and Riediger, T. (2009). Blunted fasting-induced hypothalamic activation and refeeding hyperphagia in late-onset obesity. Neuroendocrinology 90, 371-382. doi: 10.1159/000251723
15. Beverly, J. L., De Vries, M. G., Bouman, S. D., and Arseneau, L. M. (2001). Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia. Am. J. Physiol. 280, R563-R569.
16. Billington, C. J., and Levine, A. S. (1992). Hypothalamic neuropeptide Y regulation of feeding and energy metabolism. Curr. Opin. Neurobiol. 2, 847-851. doi: 10.1016/0959-4388(92)90144-A
17. Blouet, C., Jo, Y.-H., Li, X., and Schwartz, G. J. (2009). Mediobasal Hypothalamic leucine sensing regulates food intake through activation of a hypothalamus-brainstem circuit. J. Neurosci. 29, 8302-8311. doi: 10.1523/JNEUROSCI.1668-09.2009
18. Borg, M. A., Sherwin, R. S., Borg, W. P., Tamborlane, W. V., and Shulman, G. I. (1997). Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. J. Clin. Invest. 99, 361-365. doi: 10.1172/JCI119165
19. Broberger, C., Johansen, J., Johansson, C., Schalling, M., and Hokfelt, T. (1998). The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc. Natl. Acad. Sci. U.S.A. 95, 15043-15048. doi: 10.1073/pnas.95.25.15043
20. Burdakov, D., Gerasimenko, O., and 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. doi: 10.1523/JNEUROSCI.4925-04.2005
21. + channels mediate inhibition of orexin neurons by glucose. Neuron 50, 711-722. doi: 10.1016/j.neuron.2006.04.032
22. Cai, X. J., Evans, M. L., Lister, C. A., Leslie, R. A., Arch, J. R., Wilson, S., et al. (2001). Hypoglycemia activates orexin neurons and selectively increases hypothalamic orexin-B levels: responses inhibited by feeding and possibly mediated by the nucleus of the solitary tract. Diabetes 50, 105-112. doi: 10.2337/diabetes.50.1.105
23. Cai, X. J., Widdowson, P. S., Harrold, J., Wilson, S., Buckingham, R. E., Arch, J. R., et al. (1999). Hypothalamic orexin expression: modulation by blood glucose and feeding. Diabetes 48, 2132-2137. doi: 10.2337/diabetes.48.11.2132
24. Canabal, D. D., Potian, J. G., Duran, R. G., McArdle, J. J., and Routh, V. H. (2007a). Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamus.Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R592-R600. doi: 10.1152/ajpregu.00207.2007
25. Canabal, D. D., Song, Z., Potian, J. G., Beuve, A., McArdle, J. J., and Routh, V. H. (2007b). Glucose, insulin and leptin signaling pathways modulate nitric oxide (NO) synthesis in glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH). J. Physiol. Regul. Integr. Comp. Physiol. 292, R1418-R1428. doi: 10.1152/ajpregu.00216.2006
26. Cardoso, F. L., Brites, D., and Brito, M. A. (2010). Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res. Rev. 64, 328-363. doi: 10.1016/j.brainresrev.2010.05.003
27. Choi, D. L., Davis, J. F., Fitzgerald, M. E., and Benoit, S. C. (2010). The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats. Neuroscience 167, 11-20. doi: 10.1016/j.neuroscience.2010.02.002
28. Claret, M., Smith, M. A., Batterham, R. L., Selman, C., Choudury, A. I., Fryer, L. G., et al. (2007). AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J. Clin. Invest. 117, 2325-2336. doi: 10.1172/JCI31516
29. Cota, D., Proulx, K., Smith, K. A. B., Kozma, S. C., Thomas, G., Woods, S. C., et al. (2006). Hypothalamic mTOR signaling regulates food intake. Science 312, 927-930. doi: 10.1126/science.1124147
30. Cotero, V. E., and Routh, V. H. (2009). Insulin blunts the response of glucose-excited (GE) neurons in the ventrolateral-ventromedial hypothalamic nucleus (VL-VMN) to decreased glucose. Am. J. Physiol. Endocrinol. Metab. 296, E1101-E1109. doi: 10.1152/ajpendo.90932.2008
31. Cotero, V. E., Zhang, B. B., and Routh, V. H. (2009). The response of glucose-excited neurones in the ventromedial hypothalamus to decreased glucose is enhanced in a murine model of type 2 diabetes mellitus. J. Neuroendocrinol. 22, 65-74. doi: 10.1111/j.1365-2826.2009.01938.x
32. Cowley, M. A., Smart, J. L., Rubinstein, M., Cerdan, M. G., Diano, S., Horvath, T. L., et al. (2001). Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480-484. doi: 10.1038/35078085
33. Cowley, M. A., Smith, R. G., Diano, S., Tschop, M., Pronchuk, N., Grove, K. L., et al. (2003). The distribution and mechanism of action of ghrelin in the cns demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649-661. doi: 10.1016/S0896-6273(03)00063-1
34. Cruciani-Guglielmacci, C., Hervalet, A., Douared, L., Sanders, N. M., Levin, B. E., Ktorza, A., et al. (2004). Beta oxidation in the brain is required for the effects of non-esterified fatty acids on glucose-induced insulin secretion in rats. Diabetologia 47, 2032-2038. doi: 10.1007/s00125-004-1569-2
35. Cryer, P. E. (2013). Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N. Eng. J. Med. 369, 362-372. doi: 10.1056/NEJMra1215228
36. Dagogo-Jack, S. E., Craft, S., and Cryer, P. E. (1993). Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J. Clin. Invest. 91, 819-828. doi: 10.1172/JCI116302
37. De Vries, M. G., Arseneau, L. M., Lawson, M. E., and Beverly, J. L. (2003). Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. Diabetes 52, 2767-2773. doi: 10.2337/diabetes.52.11.2767
38. Diano, S., Horvath, B., Urbanski, H. F., Sotonyi, P., and Horvath, T. L. (2003). Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets. Endocrinology 144, 3774-3778. doi: 10.1210/en.2003-0274
39. Diggs-Andrews, K. A., Zhang, X., Song, Z., Daphna-Iken, D., Routh, V. H., and Fisher, S. J. (2010). Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia. Diabetes 59, 2271-2280. doi: 10.2337/db10-0401
40. Donovan, C. M., Hamilton-Wessler, M., Halter, J. B., and Bergman, R. N. (1994). Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia. Proc. Natl. Acad. Sci. U.S.A. 91, 2863-2867. doi: 10.1073/pnas.91.7.2863
41. Dunn-Meynell, A. A., Routh, V. H., Kang, L., Gaspers, L., and Levin, B. E. (2002). Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes 51, 2056-2065. doi: 10.2337/diabetes.51.7.2056
42. Dunn-Meynell, A. A., Sanders, N. M., Compton, D., Becker, T. C., Eiki, J. I, Zhang, B. B., et al. (2009). Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding. J. Neurosci. 29, 7015-7022. doi: 10.1523/JNEUROSCI.0334-09.2009
43. Elmquist, J. K. (2001). Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Physiol. Behavior. 74, 703-708. doi: 10.1016/S0031-9384(01)00613-8
44. Ferenczi, S., Zelei, E., Pintér, B., Szoke, Z., and Kovács, K. J. (2010). Differential regulation of hypothalamic neuropeptide Y hnRNA and mRNA during psychological stress and insulin-induced hypoglycemia. Mol. Cell. Endocrinol. 321, 138-145. doi: 10.1016/j.mce.2010.02.036
45. Fergani, C., Routly, J. E., Jones, D. N., Pickavance, L. C., Smith, R. F., and Dobson, H. (2014). Kisspeptin, c-Fos and CRFR Type 2 Co-expression in the hypothalamus after insulin-induced hypoglycaemia. Reprod. Domest. Anim. 49, 433-440. doi: 10.1111/rda.12293
46. Fioramonti, X., Contie, S., Song, Z., Routh, V. H., Lorsignol, A., and Penicaud, L. (2007). Characterization of glucosensing neuron subpopulations in the arcuate nucleus: integration in NPY and POMC networks? Diabetes 56, 1219-1227. doi: 10.2337/db06-0567
47. Fioramonti, X., Deak, A., Deshpande, S., Carneiro, L., Zhou, C., Sayed, N., et al. (2013). Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia. PLoS ONE 8:e68709. doi: 10.1371/journal.pone.0068709
48. + channel-independent mechanism is involved in glucose-excited neurons of mouse arcuate nucleus. Diabetes 53, 2767-2775. doi: 10.2337/diabetes.53.11.2767
49. Fioramonti, X., Marsollier, N., Song, Z., Fakira, K. A., Patel, R. M., Brown, S., et al. (2010a). Ventromedial hypothalamic nitric oxide production is necessary for hypoglycemia detection and counterregulation. Diabetes 59, 519-528. doi: 10.2337/db09-0421
50. Fioramonti, X., Song, Z., Vazirani, R. P., Beuve, A., and Routh, V. H. (2010b). Hypothalamic nitric oxide in hypoglycemia detection and counter-regulation: a two two edged sword. Antioxid. Redox Signal. 14, 505-517. doi: 10.1089/ars.2010.3331
51. Garcia, M., Millan, C., Balmaceda-Aguilera, C., Castro, T., Pastor, P., Montecinos, H., et al. (2003). Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J. Neurochem. 86, 709-724. doi: 10.1046/j.1471-4159.2003.01892.x
52. González, J. A., Jensen, L. T., Doyle, S. E., Miranda-Anaya, M., Menaker, M., Fugger, L., et al. (2009). Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons. Eur. J. Neurosci. 30, 57-64. doi: 10.1111/j.1460-9568.2009.06789.x
53. Gonzalez, J. A., Jensen, L. T., Fugger, L., and Burdakov, D. (2008). Metabolism-Independent sugar sensing in central orexin neurons. Diabetes 57, 2569-2576. doi: 10.2337/db08-0548
54. Griffond, B., Risold, P.-Y., Jacquemard, C., Colard, C., and Fellmann, D. (1999). Insulin-induced hypoglycemia increases preprohypocretin (orexin) mRNA in the rat lateral hypothalamic area. Neurosci. Lett. 262, 77-80. doi: 10.1016/S0304-3940(98)00976-8
55. Guillod-Maximin, E., Lorsignol, A., Alquier, T., and Penicaud, L. (2004). Acute intracarotid glucose injection towards the brain induces specific c-fos activation in hypothalamic nuclei: involvement of astrocytes in cerebral glucose-sensing in rats. J. Neuroendocrinol. 16, 464-471. doi: 10.1111/j.1365-2826.2004.01185.x
56. Harris, G. C., Wimmer, M., and Aston-Jones, G. (2005). A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556-559. doi: 10.1038/nature04071
57. Hevener, A. L., Bergman, R. N., and Donovan, C. M. (1997). Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes 46, 1521-1525. doi: 10.2337/diab.46.9.1521
58. Ibrahim, N., Bosch, M. A., Smart, J. L., Qiu, J., Rubinstein, M., Ronnekleiv, O. K., et al. (2003). Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinol 144, 1331-1340. doi: 10.1210/en.2002-221033
59. Joly-Amado, A., Denis, R. G. P., Castel, J., Lacombe, A., Cansell, C., Rouch, C., et al. (2012). Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J. 31, 4276-4288. doi: 10.1038/emboj.2012.250
60. Kang, L., Dunn-Meynell, A. A., Routh, V. H., Gaspers, L. D., Nagata, Y., Nishimura, T., et al. (2006). Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensing. Diabetes 55, 412-420. doi: 10.2337/diabetes.55.02.06.db05-1229
61. Kang, L., Routh, V. H., Kuzhikandathil, E. V., Gaspers, L., and Levin, B. E. (2004). Physiological and molecular properties of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53, 559. doi: 10.2337/diabetes.53.3.549
62. Kang, L., Sanders, N. M., Dunn-Meynell, A. A., Gaspers, L. D., Routh, V. H., Thomas, A. P., et al. (2008). Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons. Am. J.Physiol. Regul. Integr. Comp. Physiol. 294, R784-R792. doi: 10.1152/ajpregu.00645.2007
63. Karnani, M. M., Szabó, G., Erdélyi, F., and Burdakov, D. (2013). Lateral hypothalamic GAD65 neurons are spontaneously firing and distinct from orexin- and melanin-concentrating hormone neurons. J. Physiol. 591, 933-953. doi: 10.1113/jphysiol.2012.243493
64. Kelley, A. E., Baldo, B. A., and Pratt, W. E. (2005). A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward. J. Comp. Neurol. 493, 72-85. doi: 10.1002/cne.20769
65. 2+ signaling via protein kinase a and N-Type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52, 948-956. doi: 10.2337/diabetes.52.4.948
66. Kohno, D., Nakata, M., Maekawa, F., Fujiwara, K., Maejima, Y., Kuramochi, M., et al. (2007). Leptin suppresses ghrelin-induced activation of neuropeptide y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway. Endocrinology 148, 2251-2263. doi: 10.1210/en.2006-1240
67. 2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons. Biochem. Biophys. Res. Commun. 366, 388-392. doi: 10.1016/j.bbrc.2007.11.166
68. Langlet, F., Levin Barry, E., Luquet, S., Mazzone, M., Messina, A., Dunn-Meynell Ambrose, A., et al. (2013). Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab. 17, 607-617. doi: 10.1016/j.cmet.2013.03.004
69. Languren, G., Montiel, T., Julio-Amilpas, A., and Massieu, L. (2013). Neuronal damage and cognitive impairment associated with hypoglycemia: an integrated view. Neurochem. Int. 63, 331-343. doi: 10.1016/j.neuint.2013.06.018
70. Le Foll, C., Dunn-Meynell, A. A., Miziorko, H. M., and Levin, B. E. (2014). Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids. Diabetes 63, 1259-1269. doi: 10.2337/db13-1090
71. Le Foll, C., Dunn-Meynell, A., Musatov, S., Magnan, C., and Levin, B. E. (2013). FAT/CD36: a major regulator of neuronal fatty acid sensing and energy homeostasis in rats and mice. Diabetes 62, 2709-2716. doi: 10.2337/db12-1689
72. Leshan, R. L., Greenwald-Yarnell, M., Patterson, C. M., Gonzalez, I. E., and Myers, M. G. (2012). Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. Nat. Med. 18, 820-823. doi: 10.1038/nm.2724
73. Levin, B. E. (2000). Glucose-regulated dopamine release from substantia nigra neurons. Brain Res. 874, 158-164. doi: 10.1016/S0006-8993(00)02573-7
74. Levin, B. E. (2002). Metabolic sensors. Viewing glucosensing neurons from a broader perspective. Physiol. Behavior. 76, 397-401. doi: 10.1016/S0031-9384(02)00763-1
75. Levin, B. E., Planas, B., Routh, V. H., Hamilton, J., Stern, J. S., and Horwitz, B. A. (1993). Altered alpha 1-adrenoceptor binding in intact and adrenalectomized obese Zucker rats (fa/fa). Brain Res. 614, 146-154. doi: 10.1016/0006-8993(93)91028-Q
76. Levin, B. E., Routh, V. H., Kang, L., Sanders, N. M., and Dunn-Meynell, A. A. (2004). Neuronal glucosensing: what do we know after 50 years? Diabetes 53, 2521-2528. doi: 10.2337/diabetes.53.10.2521
77. Lindberg, D., Chen, P., and Li, C. (2013). Conditional viral tracing reveals that steroidogenic factor 1-positive neurons of the dorsomedial subdivision of the ventromedial hypothalamus project to autonomic centers of the hypothalamus and hindbrain. J. Comp. Neurol. 521, 3167-3190. doi: 10.1002/cne.23338
78. Lopez-Barneo, J. (2003). Oxygen and glucose sensing by carotid body glomus cells. Curr. Opin. Neurobiol. 13, 493-499. doi: 10.1016/S0959-4388(03)00093-X
79. López, M., Seoane, L., del Carmen García, M., Lago, F., Casanueva, F. F., Señarís, R., et al. (2000). Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus. Biochem. Biophys. Res. Commun. 269, 41-45. doi: 10.1006/bbrc.2000.2245
80. Louis, G. W., Leinninger, G. M., Rhodes, C. J., and Myers, M. G. Jr. (2010). Direct innervation and modulation of orexin neurons by lateral hypothalamic LepRb neurons. J. Neurosci. 30, 11278-11287. doi: 10.1523/JNEUROSCI.1340-10.2010
81. Lynch, R. M., Tompkins, L. S., Brooks, H. L., Dunn-Meynell, A. A., and Levin, B. E. (2000). Localization of glucokinase gene expression in the rat brain. Diabetes 49, 693-700. doi: 10.2337/diabetes.49.5.693
82. Maekawa, F., Toyoda, Y., Torii, N., Miwa, I., Thompson, R. C., Foster, D. L., et al. (2000). Localization of glucokinase-like immunoreactivity in the rat lower brain stem: for possible location of brain glucose-sensing mechanisms. Endocrinology 141, 375-384. doi: 10.1210/endo.141.1.7234
83. Magnuson, M. A. (1990). Glucokinase gene structure. Functional implications of molecular genetic studies. [Review] [31 refs]. Diabetes 39, 523-527. doi: 10.2337/diab.39.5.523
84. Marsollier, N., Kassis, N., Mezghenna, K., Soty, M., Fioramonti, X., Lacombe, A., et al. (2009). Deregulation of hepatic insulin sensitivity induced by central lipid infusion in rats is mediated by nitric oxide. PLoS ONE 4:e6649. doi: 10.1371/journal.pone.0006649
85. Marston, O. J., Hurst, P., Evans, M. L., Burdakov, D. I., and Heisler, L. K. (2011). Neuropeptide Y cells represent a distinct glucose-sensing population in the lateral hypothalamus. Endocrinology 152, 4046-4052. doi: 10.1210/en.2011-1307
86. Marty, N., Dallaporta, M., Foretz, M., Emery, M., Tarussio, D., Bady, I., et al. (2005). Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. J. Clin. Invest. 115, 3545-3553. doi: 10.1172/JCI26309
87. Matveyenko, A. V., and Donovan, C. M. (2006). Metabolic sensors mediate hypoglycemic detection at the portal vein. Diabetes 55, 1276-1282. doi: 10.2337/db05-1665
88. McNay, E. C., Fries, T. M., and Gold, P. E. (2000). Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc. Natl. Acad. Sci. U.S.A. 97, 2881-2885. doi: 10.1073/pnas.050583697
89. McNay, E. C., and Gold, P. E. (1999). Extracellular glucose concentrations in the rat hippocampus measured by zero-net-flux: effects of microdialysis flow rate, strain, and age. J. Neurochem. 72, 785-790. doi: 10.1046/j.1471-4159.1999.720785.x
90. McNay, E. C., McCarty, R. C., and Gold, P. E. (2001). Fluctuations in brain glucose concentration during behavioral testing: dissociations between brain areas and between brain and blood. Neurobiol. Learn. Mem. 75, 325-337. doi: 10.1006/nlme.2000.3976
91. Medeiros, N., Dai, L., and Ferguson, A. V. (2012). Glucose-responsive neurons in the subfornical organ of the rat-a novel site for direct CNS monitoring of circulating glucose. Neuroscience 201, 157-165. doi: 10.1016/j.neuroscience.2011.11.028
92. Melnick, I. V., Price, C. J., and Colmers, W. F. (2011). Glucosensing in parvocellular neurons of the rat hypothalamic paraventricular nucleus. Eur. J. Neurosci. 34, 272-282. doi: 10.1111/j.1460-9568.2011.07742.x
93. Migrenne, S., Cruciani-Guglielmacci, C., Kang, L., Wang, R., Rouch, C., Lefevre, A. L., et al. (2006). Fatty acid signaling in the hypothalamus and the neural control of insulin secretion. Diabetes 55, S139-S144. doi: 10.2337/db06-S017
94. Mizuno, T. M., Makimura, H., Silverstein, J., Roberts, J. L., Lopingco, T., and Mobbs, C. V. (1999). Fasting regulates hypothalamic neuropeptide, Y., agouti-related peptide, and proopiomelanocortin in diabetic mice independent of changes in leptin or insulin. Endocrinology 140, 4551-4557.
95. Mobbs, C. V., Kow, L. M., and Yan, X. J. (2001). Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses. Am. J. Physiol. 281, E649-E654.
96. Moheet, A., Kumar, A., Eberly, L. E., Kim, J., Roberts, R., and Seaquist, E. R. (2014). Hypoglycemia-Associated autonomic failure in healthy humans: comparison of two vs three periods of hypoglycemia on hypoglycemia-induced counterregulatory and symptom response 5 days later. J. Clin. Endocrinol. Metab. 99, 664-670. doi: 10.1210/jc.2013-3493
97. Moriguchi, T. S. T., Nambu, T., Yanagisawa, M., and Goto, K. (1999). Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia. Neurosci. Lett. 264, 101-104. doi: 10.1016/S0304-3940(99)00177-9
98. Mullier, A., Bouret, S. G., Prevot, V., and Dehouck, B. (2009). Differential distribution of tight junction proteins suggests a role for tanycytes in blood-hypothalamus barrier regulation in the adult mouse brain. J. Comp. Neurol. 518, 943-962. doi: 10.1002/cne.22273
99. Murphy, B. A., Fakira, K. A., Song, Z., Beuve, A., and Routh, V. H. (2009a). AMP-activated Protein Kinase (AMPK) and Nitric Oxide (NO) regulate the glucose sensitivity of ventromedial hypothalamic (VMH) glucose-inhibited (GI) neurons. Am. J. Physiol. Cell Physiol. 297, C750-C758. doi: 10.1152/ajpcell.00127.2009
100. Murphy, B. A., Fioramonti, X., Jochnowitz, N., Fakira, K., Gagen, K., Contie, S., et al. (2009b). Fasting enhances the response of arcuate neuropeptide Y (NPY)-glucose-inhibited (GI) neurons to decreased extracellular glucose. Am. J. Physiol. Cell Physiol. 296, 746-756. doi: 10.1152/ajpcell.00641.2008
101. Nakano, Y., and Oomura, Y. (1986). Feeding-related activity of glucose- and morphine-sensitive neurons in the monkey amygdala. Brain Res. 399, 167-172. doi: 10.1016/0006-8993(86)90613-X
102. Naufahu, J., Cunliffe, A. D., and Murray, J. F. (2013). The roles of melanin-concentrating hormone in energy balance and reproductive function: are they connected? Reproduction 146, R141-R150. doi: 10.1530/REP-12-0385
103. Navarro, M., Rodriquez de Fonseca, F., Alvarez, E., Chowen, J. A., Zueco, J. A., Gomez, R., et al. (1996). Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake. J. Neurochem. 67, 1982-1991. doi: 10.1046/j.1471-4159.1996.67051982.x
104. Niimi, M., Sato, M., Tamaki, M., Wada, Y., Takahara, J., and Kawanishi, K. (1995). Induction of fos protein in the rat hypothalamus elicited by insulin-induced hypoglycemia. Neurosci. Res. 23, 361-364. doi: 10.1016/0168-0102(95)00965-V
105. Oomura, Y., Kimura, K., Ooyama, H., Maeo, T., Iki, M., and Kuniyoshi, N. (1964). Reciprocal activities of the ventromedial and lateral hypothalamic area of cats. Science 143, 484-485. doi: 10.1126/science.143.3605.484
106. Oomura, Y., Ono, H., Ooyama, H., and Wayner, M. J. (1969). Glucose and osmosensitive neurons of the rat hypothalamus. Nature 222, 282-284. doi: 10.1038/222282a0
107. + in tanycytes via ATP released through connexin 43 hemichannels. Glia 60, 53-68. doi: 10.1002/glia.21246
108. Pardal, R., and Lopez-Barneo, J. (2002). Low glucose-sensing cells in the carotid body. Nat. Neurosci. 5, 197-198. doi: 10.1038/nn812
109. Parton, L. E., Ye, C. P., Coppari, R., Enriori, P. J., Choi, B., Zhang, C. Y., et al. (2007). Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228-232. doi: 10.1038/nature06098
110. Penicaud, L., Leloup, C., Lorsignol, A., Alquier, T., and Guillod, E. (2002). Brain glucose sensing mechanism and glucose homeostasis. Curr. Opin. Clin. Nutr. Metab. Care 5, 539-543. doi: 10.1097/00075197-200209000-00013
111. Perello, M., Sakata, I., Birnbaum, S., Chuang, J.-C., Osborne-Lawrence, S., Rovinsky, S. A., et al. (2010). Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol. Psychiatry 67, 880-886. doi: 10.1016/j.biopsych.2009.10.030
112. Ramonet, D., Rodriguez, M. J., Pugliese, M., and Mahy, N. (2004). Putative glucosensing property in rat and human activated microglia. Neurobiology Disease 17, 1-9. doi: 10.1016/j.nbd.2003.11.019
113. Raybould, H. E. (2007). Sensing of glucose in the gastrointestinal tract. Auton. Neurosci. 133, 86-90. doi: 10.1016/j.autneu.2007.01.006
114. Ritter, S., Li, A.-J., Wang, Q., and Dinh, T. T. (2011). Minireview: the value of looking backward: the essential role of the hindbrain in counterregulatory responses to glucose deficit. Endocrinology 152, 4019-4032. doi: 10.1210/en.2010-1458
115. Ritter, S., Llewellyn-Smith, I., and Dinh, T. T. (1998). Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-D-glucose induced metabolic challenge. Brain Res. 805, 41-54. doi: 10.1016/S0006-8993(98)00655-6
116. Rojas, J. M., and Schwartz, M. W. (2014). Control of hepatic glucose metabolism by islet and brain. Diabetes, Obes. Metab. 16, 33-40. doi: 10.1111/dom.12332
117. Roland, A. V., and Moenter, S. M. (2011). Glucosensing by GnRH Neurons: inhibition by androgens and involvement of AMP-Activated protein kinase. Mol. Endocrinol. 25, 847-858. doi: 10.1210/me.2010-0508
118. Routh, V. H., Donovan, C. M., and Ritter, S. (2013). Hypoglycemia Detection. Transl. Endocrinol. Metab. 3, 47-87. doi: 10.1210/TEAM.9781936704200.ch2
119. + channel in the ventromedial hypothalamic nucleus. Brain Res. 778, 107-119. doi: 10.1016/S0006-8993(97)01043-3
120. Sanders, N. M., Dunn-Meynell, A. A., and Levin, B. E. (2004). Third ventricular alloxan reversibly impairs glucose counterregulatory responses. Diabetes 53, 1230-1236. doi: 10.2337/diabetes.53.5.1230
121. Sawchenko, P. E. (1998). Toward a new neurobiology of energy balance, appetite, and obesity: the anatomists weigh in. J. Comp. Neurol. 402, 435-441.
122. Sayegh, A. I., Covasa, M., and Ritter, R. C. (2004). Intestinal infusions of oleate and glucose activate distinct enteric neurons in the rat. Auton. Neurosci. 115, 54-63. doi: 10.1016/j.autneu.2004.08.006
123. Sheng, Z., Santiago, A. M., Thomas, M. P., and Routh, V. H. (2014). Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry. Mol. Cell. Neurosci. 62, 30-41. doi: 10.1016/j.mcn.2014.08.001
124. Shian, L. R., and Lin, M. T. (1991). Insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia in the rat. Experientia 47, 942-944. doi: 10.1007/BF01929887
125. Shiraishi, T., Oomura, Y., Sasaki, K., and Wayner, M. J. (2000). Effects of leptin and orexin-A on food intake and feeding related hypothalamic neurons. Physiol. Behav. 71, 251-261. doi: 10.1016/S0031-9384(00)00341-3
126. Silver, I. A., and 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.
127. Song, Z., Levin, B. E., McArdle, J. J., Bakhos, N., and Routh, V. H. (2001). Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 50, 2673-2681. doi: 10.2337/diabetes.50.12.2673
128. Song, Z., and Routh, V. H. (2005). Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54, 15-22. doi: 10.2337/diabetes.54.1.15
129. Song, Z., and Routh, V. H. (2006). Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus (VMN). Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1283-R1287. doi: 10.1152/ajpregu.00148.2006
130. Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D., and Ashford, M. L. J. (1997). Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521-525. doi: 10.1038/37379
131. + channels in hypothalamic neurons of lean, but not obese rats. Nat. Neurosci. 3, 757-758. doi: 10.1038/77660
132. Stanley, S., Domingos Ana, I., Kelly, L., Garfield, A., Damanpour, S., Heisler, L., et al. (2013). Profiling of glucose-sensing neurons reveals that GHRH neurons are activated by hypoglycemia. Cell Metab. 18, 596-607. doi: 10.1016/j.cmet.2013.09.002
133. Steffens, A. B., Mogenson, G. J., and Stevenson, J. A. (1972). Blood glucose, insulin, and free fatty acids after stimulation and lesions of the hypothalamus. Am. J. Physiol. 222, 1446-1452.
134. Steffens, A. B., Scheurink, A. J., Luiten, P. G., and Bohus, B. (1988). Hypothalamic food intake regulating areas are involved in the homeostasis of blood glucose and plasma FFA levels. Physiol. Behav. 44, 581-589. doi: 10.1016/0031-9384(88)90322-8
135. Sternson, S. M., Shepherd, G. M. G., and Friedman, J. M. (2005). Topographic mapping of VMH [rarr] arcuate nucleus microcircuits and their reorganization by fasting. Nat. Neurosci. 8, 1356-1363. doi: 10.1038/nn1550
136. Stolarczyk, E., Guissard, C., Michau, A., Even, P. C., Grosfeld, A., Serradas, P., et al. (2010). Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake. Am. J. Physiol. Endocrinol. Metab. 298, E1078-E1087. doi: 10.1152/ajpendo.00737.2009
137. Straub, R. H., Cutolo, M., Buttgereit, F., and Pongratz, G. (2010). Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J. Intern. Med. 267, 543-560. doi: 10.1111/j.1365-2796.2010.02218.x
138. Szepietowska, B., Zhu, W., Chan, O., Horblitt, A., Dziura, J., and Sherwin, R. S. (2011). Modulation of β-Adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia. Diabetes60, 3154-3158. doi: 10.2337/db11-0432
139. Takahashi, K. A., and Cone, R. D. (2005). Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-Related protein neurons. Endocrinology146, 1043-1047. doi: 10.1210/en.2004-1397
140. Valassi, E., Scacchi, M., and Cavagnini, F. (2014). Neuroendocrine control of food intake. Nutr. Metab. Cardiovasc. Dis. 18, 158-168. doi: 10.1016/j.numecd.2007.06.004
141. van Dijk, G., Bottone, A. E., Strubbe, J. H., and Steffens, A. B. (1994). Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding. Brain Res. 660, 96-103. doi: 10.1016/0006-8993(94)90843-5
142. Vazirani, R. P., Fioramonti, X., and Routh, V. H. (2013). Membrane potential dye imaging of ventromedial hypothalamus neurons from adult mice to study glucose sensing. J. Vis. Exp. 81:e50861. doi: 10.3791/50861
143. Wang, Q., Liu, C., Uchida, A., Chuang, J.-C., Walker, A., Liu, T., et al. (2014). Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin. Mol. Metab. 3, 64-72. doi: 10.1016/j.molmet.2013.10.001
144. Wang, R., Cruciani-Guglielmacci, C., Migrenne, S., Magnan, C., Cotero, V. E., and Routh, V. H. (2005). The effects of oleic-acid (OA) on distinct populations of neurons in the hypothalamic arcuate nucleus (ARC) are dependent on extracellular glucose levels. J. Neurophysiol. 55, 1491-1498. doi: 10.1152/jn.00697.2005
145. Wang, R., Liu, X., Hentges, S. T., Dunn-Meynell, A. A., Levin, B. E., Wang, W., et al. (2004). The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes53, 1959-1965. doi: 10.2337/diabetes.53.8.1959
146. Warne, J. P., Varonin, J. M., Nielsen, S. S., Olofsson, L. E., Kaelin, C. B., Chua, S., et al. (2013). Coordinated regulation of hepatic energy stores by leptin and hypothalamic agouti-related protein. J. Neurosci. 33, 11972-11985. doi: 10.1523/JNEUROSCI.0830-13.2013
147. Watts, A. G., and Sanchez-Watts, G. (2002). Interactions between heterotypic stressors and corticosterone reveal integrative mechanisms for controlling corticotropin-releasing hormone gene expression in the rat paraventricular nucleus. J. Neurosci. 22, 6282-6289.
148. White, J. D. (1993). Neuropeptide Y: a central regulator of energy homeostasis. Reg. Pept. 49, 93-107.
149. Williams, R. H., Alexopoulos, H., Jensen, L. T., Fugger, L., and Burdakov, D. (2008). Adaptive sugar sensors in hypothalamic feeding circuits. Proc. Natl. Acad. Sci. U.S.A. 105, 11975-11980. doi: 10.1073/pnas.0802687105
150. Yamanaka, A., Beuckmann, C. T., Willie, J. T., Hara, J., Tsujino, N., Mieda, M., et al. (2003). Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701-713. doi: 10.1016/S0896-6273(03)00331-3
151. Yang, X. J., Kow, L. M., Funabashi, T., and Mobbs, C. V. (1999). Hypothalamic glucose sensor: similarities to and differences from pancreatic beta-cell mechanisms. Diabetes 48, 1763-1772. doi: 10.2337/diabetes.48.9.1763
152. Yang, Y., Atasoy, D., Su Helen, H., and Sternson Scott, M. (2011). Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992-1003. doi: 10.1016/j.cell.2011.07.039
153. Zhao, Y. Y., Guo, L., Du, J., and Liu, G. L. (2005). Effects of acute hypoglycemia on the orexin system in rat. Chin. Med. Sci. J. 20, 55-58.
154. Zheng, H., Patterson, L. M., and Berthoud, H.-R. (2007). Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens. J. Neurosci. 27, 11075-11082. doi: 10.1523/JNEUROSCI.3542-07.2007
155. Zhou, L., Podolsky, N., Sang, Z., Ding, Y., Fan, X., Tong, Q., et al. (2010). The medial amygdalar nucleus: a novel glucose-sensing region that modulates the counterregulatory response to hypoglycemia. Diabetes 59, 2646-2652. doi: 10.2337/db09-0995
156. Zhu, W., Czyzyk, D., Paranjape, S. A., Zhou, L., Horblitt, A., Szabó, G., et al. (2010). Glucose prevents the fall in ventromedial hypothalamic GABA that is required for full activation of glucose counterregulatory responses during hypoglycemia. Am. J. Physiol. Endocrinol. Metab. 298, E971-E977. doi: 10.1152/ajpendo.00749.2009