Multiple hypothalamic circuits sense and regulate glucose levels

American Journal of Physiology - Regulatory Integrative and Comparative Physiology

Volumn 300, Issue 1, 2011, Pages

  Karnani, Mahesh ^a   Burdakov, Denis ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

Hypocretin; Hypothalamus; Neuron; Orexin

Indexed keywords

GLUCOSE; GLUTAMIC ACID; MELANIN CONCENTRATING HORMONE; NEUROPEPTIDE Y; OREXIN; PROOPIOMELANOCORTIN; STEROIDOGENIC FACTOR 1;

FEEDING; GLUCOSE BLOOD LEVEL; GLUCOSE HOMEOSTASIS; HUNGER; HYPOTHALAMUS; LIVER; MOTIVATION; NERVE CELL; NEUROMODULATION; NONHUMAN; PANCREAS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; STRESS; SYMPATHETIC INNERVATION; THALAMUS VENTRAL NUCLEUS;

ANIMALS; GLUCOSE; HOMEOSTASIS; HUMANS; HYPOTHALAMUS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NEUROPEPTIDES; SYMPATHETIC NERVOUS SYSTEM;

EID: 78650638211     PISSN: 03636119     EISSN: 15221490     Source Type: Journal    
DOI: 10.1152/ajpregu.00527.2010     Document Type: Review

References (116)

1. Adachi A, Kobashi M, Funahashi M. Glucose-responsive neurons in the brainstem. Obes Res 3, Suppl 5: 735S-740S, 1995.
2. + channels. J Physiol 544: 429-445, 2002.
3. Anand BK, Chhina GS, Sharma KN, Dua S, Singh B. Activity of single neurons in the hypothalamic feeding centers: effect of glucose. Am J Physiol 207: 1146-1154, 1964.
4. Antunes VR, Brailoiu GC, Kwok EH, Scruggs P, Dun NJ. Orexins/ hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro. Am J Physiol Regul Integr Comp Physiol 281: R1801-R1807, 2001.
5. Arluison M, Quignon M, Nguyen P, Thorens B, Leloup C, Penicaud L. Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain-an immunohistochemical study. J Chem Neuroanat 28: 117-136, 2004. (Pubitemid 39336524)
6. Ashcroft FM. KATP channels and insulin secretion: a key role in health and disease. Biochem Soc Trans 34: 243-246, 2006.
7. Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic β-cell. Prog Biophys Mol Biol 54: 87-143, 1989.
8. Astrand A, Bohlooly YM, Larsdotter S, Mahlapuu M, Andersen H, Tornell J, Ohlsson C, Snaith M, Morgan DG. Mice lacking melaninconcentrating hormone receptor 1 demonstrate increased heart rate associated with altered autonomic activity. Am J Physiol Regul Integr Comp Physiol 287: R749-R758, 2004.
9. Ballanyi K. Protective role of neuronal KATP channels in brain hypoxia. J Exp Biol 207: 3201-3212, 2004.
10. Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale W, Sawchenko PE. The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J Comp Neurol 319: 218-245, 1992.
11. Borg MA, Sherwin RS, Borg WP, Tamborlane WV, Shulman GI. Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. J Clin Invest 99: 361-365, 1997.
12. Borg WP, Sherwin RS, During MJ, Borg MA, Shulman GI. Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Diabetes 44: 180-184, 1995.
13. Borgland SL, Chang SJ, Bowers MS, Thompson JL, Vittoz N, Floresco SB, Chou J, Chen BT, Bonci A. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J Neurosci 29: 11215-11225, 2009.
14. Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49: 589-601, 2006.
15. Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Lagu B, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I, Blackburn TP, Branchek TA, Gerald C, Vaysse PJ, Forray C. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med 8: 825-830, 2002.
16. Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102: 19168-19173, 2005.
17. Brundin L, Bjorkqvist M, Petersen A, Traskman-Bendz L. Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. Eur Neuropsychopharmacol 17: 573-579, 2007.
18. + channels stimulated by glucose: a new energy-sensing pathway. Pflügers Arch 454: 19-27, 2007.
19. Burdakov D, Gerasimenko O, Verkhratsky A. Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin- concentrating hormone and orexin neurons in situ. J Neurosci 25: 2429-2433, 2005.
20. Burdakov D, Lesage F. Glucose-induced inhibition: how many ionic mechanisms? Acta Physiol (Oxf), 2009.
21. Burdakov D, Luckman SM, Verkhratsky A. Glucose-sensing neurons of the hypothalamus. Philos Trans R Soc Lond B Biol Sci 360: 2227-2235, 2005.
22. Cai XJ, Evans ML, Lister CA, Leslie RA, Arch JR, Wilson S, Williams G. 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, 2001.
23. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: 437-451, 1999.
24. Chen Y, Hu C, Hsu CK, Zhang Q, Bi C, Asnicar M, Hsiung HM, Fox N, Slieker LJ, Yang DD, Heiman ML, Shi Y. Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology 143: 2469-2477, 2002.
25. Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, Clements M, Al-Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford ML, Carling D, Withers DJ. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 117: 2325-2336, 2007.
26. Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ. The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 25, Suppl 5: S63-S67, 2001.
27. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411: 480-484, 2001.
28. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia- Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37: 649-661, 2003.
29. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN II, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95: 322-327, 1998.
30. Dunn-Meynell AA, Routh VH, Kang L, Gaspers L, Levin BE. Glucokinase is the likely mediator of glucosensing in both glucoseexcited and glucose-inhibited central neurons. Diabetes 51: 2056-2065, 2002.
31. Dunn-Meynell AA, Sanders NM, Compton D, Becker TC, Eiki J, Zhang BB, Levin BE. Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding. J Neurosci 29: 7015-7022, 2009.
32. Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, Saper CB, Scammell TE. Fos expression in orexin neurons varies with behavioral state. J Neurosci 21: 1656-1662, 2001.
33. Ferguson AV, Samson WK. The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function. Front Neuroendocrinol 24: 141-150, 2003.
34. Fioramonti X, Contie S, Song Z, Routh VH, Lorsignol A, Penicaud L. Characterization of glucosensing neuron subpopulations in the arcuate nucleus: integration in neuropeptide Y and pro-opio melanocortin networks? Diabetes 56: 1219-1227, 2007.
35. Ganong WF. Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol 27: 422-427, 2000.
36. Geerling JC, Mettenleiter TC, Loewy AD. Orexin neurons project to diverse sympathetic outflow systems. Neuroscience 122: 541-550, 2003.
37. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, Marsh DJ, Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ. The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci 25: 2933-2940, 2005.
38. Gonzalez JA, Jensen LT, Doyle SE, Miranda-Anaya M, Menaker M, Fugger L, Bayliss DA, Burdakov D. 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, 2009.
39. Gonzalez JA, Jensen LT, Fugger L, Burdakov D. Metabolism-independent sugar sensing in central orexin neurons. Diabetes 57: 2569-2576, 2008.
40. Gonzalez JA, Reimann F, Burdakov D. Dissociation between sensing and metabolism of glucose in sugar sensing neurones. J Physiol 587: 41-48, 2009.
41. + channels. J Neurosci 29: 2528-2533, 2009.
42. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30: 345-354, 2001.
43. Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29: 571-577, 2006.
44. Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437: 556-559, 2005.
45. Hevener AL, Bergman RN, Donovan CM. Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia. Diabetes 49: 8-12, 2000.
46. Ibrahim N, Bosch MA, Smart JL, Qiu J, Rubinstein M, Ronnekleiv OK, Low MJ, Kelly MJ. Hypothalamic proopiomelanocortin neurons are glucose responsive and express KATP channels. Endocrinology 144: 1331-1340, 2003.
47. Ito N, Yabe T, Gamo Y, Nagai T, Oikawa T, Yamada H, Hanawa T. Icv administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation. Neuroscience 157: 720-732, 2008.
48. Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, Bowling AC, Newman HC, Jenkins AL, Goff DV. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr 34: 362-366, 1981.
49. Kang L, Routh VH, Kuzhikandathil EV, Gaspers LD, Levin BE. Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53: 549-559, 2004.
50. Karschin C, Ecke C, Ashcroft FM, Karschin A. Overlapping distribution of KATP channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain. FEBS Lett 401: 59-64, 1997.
51. Kerman IA, Bernard R, Rosenthal D, Beals J, Akil H, Watson SJ. Distinct populations of presympathetic-premotor neurons express orexin or melanin-concentrating hormone in the rat lateral hypothalamus. J Comp Neurol 505: 586-601, 2007.
52. Kiyashchenko LI, Mileykovskiy BY, Maidment N, Lam HA, Wu MF, John J, Peever J, Siegel JM. Release of hypocretin (orexin) during waking and sleep states. J Neurosci 22: 5282-5286, 2002.
53. Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B. The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148: 752-759, 2006.
54. Levin BE. Neuronal glucose sensing: still a physiological orphan? Cell Metab 6: 252-254, 2007.
55. Liu XH, Morris R, Spiller D, White M, Williams G. Orexin a preferentially excites glucose-sensitive neurons in the lateral hypothalamus of the rat in vitro. Diabetes 50: 2431-2437, 2001. (Pubitemid 33642758)
56. Llewellyn-Smith IJ, Martin CL, Marcus JN, Yanagisawa M, Minson JB, Scammell TE. Orexin-immunoreactive inputs to rat sympathetic preganglionic neurons. Neurosci Lett 351: 115-119, 2003.
57. Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen AS, Guan XM, Jiang MM, Feng Y, Camacho RE, Shen Z, Frazier EG, Yu H, Metzger JM, Kuca SJ, Shearman LP, Gopal- Truter S, MacNeil DJ, Strack AM, MacIntyre DE, Van der Ploeg LH, Qian S. Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci USA 99: 3240-3245, 2002.
58. Marty N, Dallaporta M, Thorens B. Brain glucose sensing, counterregulation, and energy homeostasis. Physiology (Bethesda) 22: 241-251, 2007.
59. + channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4: 507-512, 2001.
60. Mobbs CV, Kow LM, Yang XJ. Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses. Am J Physiol Endocrinol Metab 281: E649-E654, 2001.
61. Moriguchi T, Sakurai T, Nambu T, Yanagisawa M, Goto K. 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, 1999.
62. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 443: 289-295, 2006.
63. Mountjoy PD, Rutter GA. Glucose sensing by hypothalamic neurons and pancreatic islet cells: AMPle evidence for common mechanisms? Exp Physiol 92: 311-319, 2007.
64. Mullier A, Bouret SG, Prevot V, Dehouck B. 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, 2010.
65. 2+ in orexin neurons of the rat lateral hypothalamus. Neurosci Lett 309: 165-168, 2001.
66. Muroya S, Yada T, Shioda S, Takigawa M. Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neurosci Lett 264: 113-116, 1999.
67. Nonogaki K. New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43: 533-549, 2000.
68. Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, Mc- Kinley MJ. The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience 110: 515-526, 2002.
69. Oomura Y, Ono T, Ooyama H, Wayner MJ. Glucose and osmosensitive neurones of the rat hypothalamus. Nature 222: 282-284, 1969.
70. Oomura Y, Ooyama H, Sugimori M, Nakamura T, Yamada Y. Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus. Nature 247: 284-286, 1974.
71. Parsons MP, Hirasawa M. ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal. J Neurosci 30: 8061-8070, 2010.
72. Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, Xu C, Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley MA, Lowell BB. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449: 228-232, 2007.
73. Pellerin L. How astrocytes feed hungry neurons. Mol Neurobiol 32: 59-72, 2005.
74. Peruzzo B, Pastor FE, Blazquez JL, Schobitz K, Pelaez B, Amat P, Rodriguez EM. A second look at the barriers of the medial basal hypothalamus. Exp Brain Res 132: 10-26, 2000.
75. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18: 9996-10015, 1998.
76. Presse F, Sorokovsky I, Max JP, Nicolaidis S, Nahon JL. Melaninconcentrating hormone is a potent anorectic peptide regulated by fooddeprivation and glucopenia in the rat. Neuroscience 71: 735-745, 1996.
77. Puschel GP. Control of hepatocyte metabolism by sympathetic and parasympathetic hepatic nerves. Anat Rec A Discov Mol Cell Evol Biol 280: 854-867, 2004.
78. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos-Flier E. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380: 243-247, 1996.
79. Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble FM. Glucose sensing in L cells: a primary cell study. Cell Metab 8: 532-539, 2008.
80. Ritter RC, Slusser PG, Stone S. Glucoreceptors controlling feeding and blood glucose: location in the hindbrain. Science 213: 451-452, 1981.
81. Rorsman P, Salehi SA, Abdulkader F, Braun M, MacDonald PE. KATP-channels and glucose-regulated glucagon secretion. Trends Endocrinol Metab 19: 277-284, 2008.
82. Rossi M, Choi SJ, O'Shea D, Miyoshi T, Ghatei MA, Bloom SR. Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology 138: 351-355, 1997.
83. Routh VH. Glucose-sensing neurons: are they physiologically relevant? Physiol Behav 76: 403-413, 2002.
84. Routh VH. Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) and hypoglycemia-associated autonomic failure (HAAF). Diabetes Metab Res Rev 19: 348-356, 2003.
85. Routh VH, Song Z, Liu X. The role of glucosensing neurons in the detection of hypoglycemia. Diabetes Technol Ther 6: 413-421, 2004.
86. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 573-585, 1998.
87. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, and Baskin DG. Central nervous system control of food intake. Nature 404: 661-671, 2000.
88. Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396: 670-674, 1998.
89. Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H. Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol Regul Integr Comp Physiol 277: R1780-R1785, 1999.
90. Shiuchi T, Haque MS, Okamoto S, Inoue T, Kageyama H, Lee S, Toda C, Suzuki A, Bachman ES, Kim YB, Sakurai T, Yanagisawa M, Shioda S, Imoto K, Minokoshi Y. Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system. Cell Metab 10: 466-480, 2009.
91. Siegel JM. Hypocretin (orexin): role in normal behavior and neuropathology. Annu Rev Psychol 55: 125-148, 2004.
92. Silver IA, Erecinska M. 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, 1994.
93. Smith GP, Epstein AN. Increased feeding in response to decreased glucose utilization in the rat and monkey. Am J Physiol 217: 1083-1087, 1969.
94. Song Z, Routh VH. Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus. Am J Physiol Regul Integr Comp Physiol 291: R1283-R1287, 2006.
95. Stanley S, Pinto S, Segal J, Perez CA, Viale A, DeFalco J, Cai X, Heisler LK, Friedman JM. Identification of neuronal subpopulations that project from hypothalamus to both liver and adipose tissue polysynaptically. Proc Natl Acad Sci USA 107: 7024-7029.
96. Sternson SM, Shepherd GM, Friedman JM. Topographic mapping of VMH -> arcuate nucleus microcircuits and their reorganization by fasting. Nat Neurosci 8: 1356-1363, 2005.
97. Sutcliffe JG, de Lecea L. The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3: 339-349, 2002.
98. Suzuki M, Beuckmann CT, Shikata K, Ogura H, Sawai T. Orexin-A (hypocretin-1) is possibly involved in generation of anxiety-like behavior. Brain Res 1044: 116-121, 2005.
99. Taheri S, Zeitzer JM, Mignot E. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci 25: 283-313, 2002.
100. Taylor MM, Samson WK. The other side of the orexins: endocrine and metabolic actions. Am J Physiol Endocrinol Metab 284: E13-E17, 2003.
101. Thorens B. GLUT2 in pancreatic and extra-pancreatic gluco-detection. Mol Membr Biol 18: 265-273, 2001.
102. Tolhurst G, Reimann F, Gribble FM. Nutritional regulation of glucagon- like peptide-1 secretion. J Physiol 587: 27-32, 2009.
103. Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B, Kramer MD, Yu J, Yang Z, Christiansen LM, Lee CE, Choi CS, Zigman JM, Shulman GI, Sherwin RS, Elmquist JK, Lowell BB. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab 5: 383-393, 2007.
104. Tsuneki H, Wada T, Sasaoka T. Role of orexin in the regulation of glucose homeostasis. Acta Physiol (Oxf) 198: 335-348, 2010.
105. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci 7: 493-494, 2004.
106. Verret L, Goutagny R, Fort P, Cagnon L, Salvert D, Leger L, Boissard R, Salin P, Peyron C, Luppi PH. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci 4: 19, 2003.
107. Wang J, Osaka T, Inoue S. Energy expenditure by intracerebroventricular administration of orexin to anesthetized rats. Neurosci Lett 315: 49-52, 2001.
108. Williams RH, Alexopoulos H, Jensen LT, Fugger L, Burdakov D. Adaptive sugar sensors in hypothalamic feeding circuits. Proc Natl Acad Sci USA 105: 11975-11980, 2008.
109. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24: 429-458, 2001.
110. Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38: 701-713, 2003.
111. Yang XJ, Kow LM, Funabashi T, Mobbs CV. Hypothalamic glucose sensor: similarities to and differences from pancreatic β-cell mechanisms. Diabetes 48: 1763-1772, 1999.
112. Yi CX, Serlie MJ, Ackermans MT, Foppen E, Buijs RM, Sauerwein HP, Fliers E, Kalsbeek A. A major role for perifornical orexin neurons in the control of glucose metabolism in rats. Diabetes 58: 1998-2005, 2009.
113. Yuan H, Yamada K, Inagaki N. Glucose sensitivity in mouse substantia nigra pars reticulata neurons in vitro. Neurosci Lett 355: 173-176, 2004. (Pubitemid 38368731)
114. Zhang R, Dhillon H, Yin H, Yoshimura A, Lowell BB, Maratos-Flier E, Flier JS. Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight. Endocrinology 149: 5654-5661, 2008.
115. Zhou D, Shen Z, Strack AM, Marsh DJ, Shearman LP. Enhanced running wheel activity of both Mch1r- and Pmch-deficient mice. Regul Pept 124: 53-63, 2005.
116. Zhu W, Czyzyk D, Paranjape SA, Zhou L, Horblitt A, Szabo G, Seashore MR, Sherwin RS, Chan O. 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, 2010.