Hypothalamic Glucose-sensing: Role of Glia-to-Neuron Signaling

Abstract

The hypothalamus senses hormones and nutrients in order to regulate energy balance. In particular, detection of hypothalamic glucose levels has been shown to regulate both feeding behavior and peripheral glucose homeostasis, and impairment of this regulatory system is believed to be involved in the development of obesity and diabetes. Several data clearly demonstrate that glial cells are key elements in the perception of glucose, constituting with neurons a “glucose-sensing unit”. Characterization of this interplay between glia and neurons represents an exciting challenge, and will undoubtedly contribute to identify new candidates for therapeutic intervention. The purpose of this review is to summarize the current data that stress the importance of glia in central glucose-sensing. The nature of the glia-to-neuron signaling is discussed, with a special focus on the endozepine ODN, a potent anorexigenic peptide that is highly expressed in hypothalamic glia.

Key words

glial cells - glucose - endozepine

• References

• 1 Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, Abusnana S, Goldstone AP, Russell SH, Stanley SA, Smith DM, Yagaloff K, Ghatei MA, Bloom SR. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 1998; 139: 4428-4431
• 2 Stanley BG, Leibowitz SF. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA 1985; 82: 3940-3943
• 3 Blouet C, Schwartz GJ. Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 2010; 209: 1-12
• 4 Agulhon C, Sun MY, Murphy T, Myers T, Lauderdale K, Fiacco TA. Calcium signaling and gliotransmission in normal vs. reactive astrocytes. Front Pharmacol 2012; 3: 139
• 5 Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends on release of D-serine from astrocytes. Nature 2010; 463: 232-236
• 6 Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 2005; 6: 626-640
• 7 Young JK, McKenzie JC. GLUT2 immunoreactivity in Gomori-positive astrocytes of the hypothalamus. J Histochem Cytochem 2004; 52: 1519-1524
• 8 Rodríguez EM, Blázquez JL, Pastor FE, Peláez B, Peña P, Peruzzo B, Amat P. Hypothalamic tanycytes: a key component of brain-endocrine interaction. Int Rev Cytol 2005; 247: 89-164
• 9 Mayer J. Glucostatic mechanism of regulation of food intake. Obes Res 1953; 4: 493-496
• 10 Louis-Sylvestre J, Le Magnen J. Fall in blood glucose level precedes meal onset in free-feeding rats. Neurosci Biobehav Rev 1980; 4: 13-15
• 11 Campfield LA, Brandon P, Smith FJ. On-line continuous measurement of blood glucose and meal pattern in free-feeding rats: the role of glucose. in meal initiation. Brain Res Bull 1985; 14: 605-616
• 12 Davis JD, Wirtshafter D, Asin KE, Brief D. Sustained intracerebroventricular infusion of brain fuels reduces body weight and food intake in rats. Science 1981; 212: 81-83
• 13 Kurata K, Fujimoto K, Sakata T, Etou H, Fukagawa K. D-glucose suppression of eating after intra-third ventricle infusion in rat. Physiol Behav 1986; 37: 615-620
• 14 Panksepp J, Rossi J. D-glucose infusions into the basal ventromedial hypothalamus and feeding. Behav Brain Res 1981; 3: 381-392
• 15 Bady I, Marty N, Dallaporta M, Emery M, Gyger J, Tarussio D, Foretz M, Thorens B. Evidence from glut2-null mice that glucose is a critical physiological regulator of feeding. Diabetes 2006; 55: 988-995
• 16 Marty N, Dallaporta M, Foretz M, Emery M, Tarussio D, Bady I, Binnert C, Beermann F, Thorens B. Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. J Clin Invest 2005; 115: 3545-3553
• 17 Miselis RR, Epstein AN. Feeding induced by intracerebroventricular 2-deoxy-D-glucose in the rat. Am J Physiol 1975; 229: 1438-1447
• 18 Smith GP, Epstein AN. Increased feeding in response to decreased glucose utilization in the rat and monkey. Am J Physiol 1969; 217: 1083-1087
• 19 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 1997; 99: 361-365
• 20 Borg WP, Sherwin RS, During MJ, Borg MA, Shulman GI. Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Diabetes 1995; 44: 180-184
• 21 Guillod-Maximin E, Lorsignol A, Alquier T, Pénicaud L. 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 2004; 16: 464-471
• 22 Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 2005; 309: 943-947
• 23 Vidarsdottir S, Smeets PA, Eichelsheim DL, van Osch MJ, Viergever MA, Romijn JA, van der Grond J, Pijl H. Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Diabetes 2007; 56: 2547-2550
• 24 Anand BK, Chhina GS, Singh B. Effect of glucose on the activity of hypothalamic “feeding centers”. Science 1962; 138: 597-598
• 25 Oomura Y, Ono T, Ooyama H, Wayner MJ. Glucose and osmosensitive neurones of the rat hypothalamus. Nature 1969; 222: 282-284
• 26 Hiriart M, Aguilar-Bryan L.. Channel regulation of glucose sensing in the pancreatic beta-cell. Am J Physiol Endocrinol Metab 2008; 295: 1298-1306
• 27 Roncero I, Alvarez E, Vázquez P, Blázquez E. Functional glucokinase isoforms are expressed in rat brain. J Neurochem 2000; 74: 1848-1857
• 28 Lynch RM, Tompkins LS, Brooks HL, Dunn-Meynell AA, Levin BE. Localization of glucokinase gene expression in the rat brain. Diabetes 2000; 49: 693-700
• 29 Dunn-Meynell AA, Routh VH, Kang L, Gaspers L, Levin BE. Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes 2002; 51: 2056-2065
• 30 Mounien L, Marty N, Tarussio D, Metref S, Genoux D, Preitner F, Foretz M, Thorens B. Glut2-dependent glucose-sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons. FASEB J 2010; 24: 1747-1758
• 31 Garcia MA, Millan C, Balmaceda-Aguilera C, Castro T, Pastor P, Montecinos H, Reinicke K, Zuniga F, Vera JC, Onate SA, Nualart F. Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem 2003; 86: 709-724
• 32 Maekawa F, Toyoda Y, Torii N, Miwa I, Thompson RC, Foster DL, Tsukahara S, Tsukamura H, Maeda K. Localization of glucokinase-like immunoreactivity in the rat lower brain stem: for possible location of brain glucose-sensing mechanisms. Endocrinology 2000; 141: 375-384
• 33 Millan C, Martinez F, Cortes-Campos C, Lizama I, Yanez MJ, Llanos P, Reinicke K, Rodriguez F, Peruzzo B, Nualart F, Garcia MA. Glial glucokinase expression in adult and post-natal development of the hypothalamic region. ASN Neuro 2010; 2: e00035
• 34 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 2010; 518: 943-962
• 35 Langlet F, Levin BE, Luquet S, Mazzone M, Messina A, Dunn-Meynell AA, Balland E, Lacombe A, Mazur D, Carmeliet P, Bouret SG, Prevot V, Dehouck B. Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab 2013; 17: 607-617
• 36 Young JK, Baker JH, Montes MI. The brain response to 2-deoxy glucose is blocked by a glial drug. Pharmacol Biochem Behav 2000; 67: 233-239
• 37 Lenzen S, Brand FH, Panten U. Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition. Br J Pharmacol 1988; 95: 851-859
• 38 Sanders NM, Dunn-Meynell AA, Levin BE. Third ventricular alloxan reversibly impairs glucose counterregulatory responses. Diabetes 2004; 53: 1230-1236
• 39 Chari M, Yang CS, Lam CK, Lee K, Mighiu P, Kokorovic A, Cheung GW, Lai TY, Wang PY, Lam TK. Glucose transporter-1 in the hypothalamic glial cells mediates glucose sensing to regulate glucose production in vivo. Diabetes 2011; 60: 1901-1906
• 40 Frayling C, Britton R, Dale N. ATP-mediated glucosensing by hypothalamic tanycytes. J Physiol 2011; 589: 2275-2286
• 41 Orellana JA, Saez PJ, Cortes-Campos C, Elizondo RJ, Shoji KF, Contreras-Duarte S, Figueroa V, Velarde V, Jiang JX, Nualart F, Saez JC, Garcia MA. Glucose increases intracellular free Ca^2 + in tanycytes via ATP released through connexin 43 hemichannels. Glia 2012; 60: 53-68
• 42 Borg MA, Tamborlane WV, Shulman GI, Sherwin RS. Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 2003; 52: 663-666
• 43 Cortes-Campos C, Elizondo R, Llanos P, Uranga RM, Nualart F, Garcia MA. MCT expression and lactate influx/efflux in tanycytes involved in glia-neuron metabolic interaction. PLoS One 2011; 6: e16411
• 44 Diano S, Naftolin F, Goglia F, Csernus V, Horvath TL. Monosynaptic pathway between the arcuate nucleus expressing glial type II iodothyronine 5'-deiodinase mRNA and the median eminence-projective TRH cells of the rat paraventricular nucleus. J Neuroendocrinol 1998; 10: 731-742
• 45 Diano S, Naftolin F, Goglia F, Horvath TL. Fasting-induced increase in type II iodothyronine deiodinase activity and messenger ribonucleic acid levels is not reversed by thyroxine in the rat hypothalamus. Endocrinology 1998; 139: 2879-2884
• 46 Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB, Diano S. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab 2007; 5: 21-33
• 47 Coppola A, Meli R, Diano S. Inverse shift in circulating corticosterone and leptin levels elevates hypothalamic deiodinase type 2 in fasted rats. Endocrinology 2005; 146: 2827-2833
• 48 Shinoda H, Marini AM, Cosi C, Schwartz JP. Brain region and gene specificity of neuropeptide gene expression in cultured astrocytes. Science 1989; 245: 415-417
• 49 Oomura Y, Sasaki K, Suzuki K, Muto T, Li AJ, Ogita Z, Hanai K, Tooyama I, Kimura H, Yanaihara N. A new brain glucosensor and its physiological significance. Am J Clin Nutr. 1992; 55: 278S-282S
• 50 Shen L, Tso P, Wang DQ, Woods SC, Davidson WS, Sakai R, Liu M. Up-regulation of apolipoprotein E by leptin in the hypothalamus of mice and rats. Physiol Behav 2009; 98: 223-228
• 51 Shen L, Wang DQ, Tso P, Jandacek RJ, Woods SC, Liu M. Apolipoprotein E reduces food intake via PI3K/Akt signaling pathway in the hypothalamus. Physiol Behav 2011; 105: 124-128
• 52 Tonon MC, Leprince J, Morin F, Gandolfo P, Compère V, Pelletier G, Malagon M, Vaudry H. Endozepines. In: Kastin AJ. ed. Handbook of Biologically Active Peptides. Amsterdam: Elsevier; 2013: 760-765
• 53 Ferrero P, Santi MR, Conti-Tronconi B, Costa E, Guidotti A. Study of an octadecaneuropeptide derived from diazepam binding inhibitor (DBI): biological activity and presence in rat brain. Proc Natl Acad Sci USA 1986; 83: 827-831
• 54 Slobodyansky E, Guidotti A, Wambebe C, Berkovich A, Costa E. Isolation and characterization of a rat brain triakontatetraneuropeptide, a posttranslational product of diazepam binding inhibitor: specific action at the Ro 5-4864 recognition site. J Neurochem 1989; 53: 1276-1284
• 55 Compère V, Lanfray D, Castel H, Morin F, Leprince J, Dureuil B, Vaudry H, Pelletier G, Tonon MC. Acute food deprivation reduces expression of diazepam-binding inhibitor, the precursor of the anorexigenic octadecaneuropeptide ODN, in mouse glial cells. J Mol Endocrinol 2010; 44: 295-299
• 56 Malagon M, Vaudry H, Van Strien F, Pelletier G, Gracia-Navarro F, Tonon MC. Ontogeny of diazepam-binding inhibitor-related peptides (endozepines) in the rat brain. Neuroscience 1993; 57: 777-786
• 57 Tonon MC, Désy L, Nicolas P, Vaudry H, Pelletier G. Immunocytochemical localization of the endogenous benzodiazepine ligand octadecaneuropeptide (ODN) in the rat brain. Neuropeptides 1990; 15: 17-24
• 58 Loomis WF, Behrens MM, Williams ME, Anjard C. Pregnenolone sulfate and cortisol induce secretion of acyl-CoA-binding protein and its conversion into endozepines from astrocytes. J Biol Chem 2010; 285: 21359-21365
• 59 Masmoudi O, Gandolfo P, Leprince J, Vaudry D, Fournier A, Patte-Mensah C, Vaudry H, Tonon MC. Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates endozepine release from cultured rat astrocytes via a PKA-dependent mechanism. FASEB J 2003; 17: 17-27
• 60 Patte C, Gandolfo P, Leprince J, Thoumas JL, Fontaine M, Vaudry H, Tonon MC. GABA inhibits endozepine release from cultured rat astrocytes. Glia 1999; 25: 404-411
• 61 Lafon-Cazal M, Adjali O, Galéotti N, Poncet J, Jouin P, Homburger V, Bockaert J, Marin P. Proteomic analysis of astrocytic secretion in the mouse. Comparison with the cerebrospinal fluid proteome. J Biol Chem 2003; 278: 24438-24448
• 62 Bruns C, McCaffery JM, Curwin AJ, Duran JMM, Malhotra V. Biogenesis of a novel compartment for autophagosome-mediated unconventional protein secretion. J Cell Biol 2011; 195: 979-992
• 63 do Rego JC, Orta MH, Leprince J, Tonon MC, Vaudry H, Costentin J. Pharmacological characterization of the receptor mediating the anorexigenic action of the octadecaneuropeptide: evidence for an endozepinergic tone regulating food intake. Neuropsychopharmacology 2007; 32: 1641-1648
• 64 Lanfray D, Arthaud S, Ouellet J, Compère V, Do Rego JL, Leprince J, Lefranc B, Castel H, Bouchard C, Monge-Roffarello B, Richard D, Pelletier G, Vaudry H, Tonon MC, Morin F. Gliotransmission and brain glucose sensing: critical role of endozepines. Diabetes 2013; 62: 801-810
• 65 Matsuda K, Wada K, Miura T, Maruyama K, Shimakura SI, Uchiyama M, Leprince J, Tonon MC, Vaudry H. Effect of the diazepam-binding inhibitor-derived peptide, octadecaneuropeptide, on food intake in goldfish. Neuroscience 2007; 150: 425-432
• 66 de Mateos-Verchere JG, Leprince J, Tonon MC, Vaudry H, Costentin J. The octadecaneuropeptide [diazepam-binding inhibitor (33–50)] exerts potent anorexigenic effects in rodents. Eur J Pharmacol 2001; 414: 225-231
• 67 Gandolfo P, Patte C, Leprince J, Thoumas JL, Vaudry H, Tonon MC. The stimulatory effect of the octadecaneuropeptide (ODN) on cytosolic Ca²⁺ in rat astrocytes is not mediated through classical benzodiazepine receptors. Eur J Pharmacol 1997; 322: 275-281
• 68 Leprince J, Oulyadi H, Vaudry D, Masmoudi O, Gandolfo P, Patte C, Costentin J, Fauchère JL, Davoust D, Vaudry H, Tonon MC. Synthesis, conformational analysis and biological activity of cyclic analogs of the octadecaneuropeptide ODN. Design of a potent endozepine antagonist. Eur J Biochem 2001; 268: 6045-6057
• 69 Compère V, Li S, Leprince J, Tonon MC, Vaudry H, Pelletier G. Effect of intracerebroventricular administration of the octadecaneuropeptide on the expression of pro-opiomelanocortin, neuropeptide Y and corticotropin-releasing hormone mRNAs in rat hypothalamus. J Neuroendocrinol 2003; 15: 197-203
• 70 Fisher E, Nitz I, Gieger C, Grallert H, Gohlke H, Lindner I, Dahm S, Boeing H, Burwinkel B, Rathmann W, Wichmann HE, Schrezenmeir J, Illig T, Doring F. Association of acyl-CoA-binding protein (ACBP) single nucleotide polymorphisms and type 2 diabetes in two German study populations. Mol Nutr Food Res 2007; 51: 178-184
• 71 Conti E, Tremolizzo L, Bomba M, Uccellini O, Rossi MS, Raggi ME, Neri F, Ferrarese C, Nacinovich R. Reduced fasting plasma levels of diazepam-binding inhibitor in adolescents with anorexia nervosa. Int J Eat Disord 2013; [Epub ahead of print]