Plasticity of the Melanocortin System: Determinants and Possible Consequences on Food Intake

Frontiers in Endocrinology

Volumn 6, Issue , 2015, Pages

  Nuzzaci, Danaé ^a   Laderrière, Amélie ^a   Lemoine, Aleth ^a   Nédélec, Emmanuelle ^a   Pénicaud, Luc ^a   Rigault, Caroline ^a   Benani, Alexandre ^a  

^a CENTRE DES SCIENCES DU GOÛT ET DE L ALIMENTATION   (France)

Author keywords

AgRP neurons; food intake; melanocortin system; obesity; POMC neurons; synaptic plasticity

Indexed keywords

EID: 84977933915     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2015.00143     Document Type: Review

References (119)

1. Holtmaat A Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci (2009) 10:647–58.10.1038/nrn269919693029
2. Berthoud HR. Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr Opin Neurobiol (2011) 21:888–96.10.1016/j.conb.2011.09.00421981809
3. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci (2005) 8:571–8.10.1038/nn145515856065
4. Ellacott KL Cone RD. The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models. Philos Trans R Soc Lond B Biol Sci (2006) 361:1265–74.10.1098/rstb.2006.186116815803
5. Garfield AS Lam DD Marston OJ Przydzial MJ Heisler LK. Role of central melanocortin pathways in energy homeostasis. Trends Endocrinol Metab (2009) 20:203–15.10.1016/j.tem.2009.02.00219541496
6. Xu Y Elmquist JK Fukuda M. Central nervous control of energy and glucose balance: focus on the central melanocortin system. Ann N Y Acad Sci (2011) 1243:1–14.10.1111/j.1749-6632.2011.06248.x22211889
7. Mountjoy KG. Pro-opiomelanocortin (POMC) neurones, POMC-derived peptides, melanocortin receptors and obesity: how understanding of this system has changed over the last decade. J Neuroendocrinol (2015) 27:406–18.10.1111/jne.1228525872650
8. Mountjoy KG Mortrud MT Low MJ Simerly RB Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol (1994) 8:1298–308.10.1210/me.8.10.12987854347
9. Kishi T Aschkenasi CJ Lee CE Mountjoy KG Saper CB Elmquist JK. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol (2003) 457:213–35.10.1002/cne.1045412541307
10. Liu H Kishi T Roseberry AG Cai X Lee CE Montez JM et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci (2003) 23:7143–54.12904474
11. Begriche K Marston OJ Rossi J Burke LK Mcdonald P Heisler LK et al. Melanocortin-3 receptors are involved in adaptation to restricted feeding. Genes Brain Behav (2012) 11:291–302.10.1111/j.1601-183X.2012.00766.x22353545
12. Renquist BJ Murphy JG Larson EA Olsen D Klein RF Ellacott KL et al. Melanocortin-3 receptor regulates the normal fasting response. Proc Natl Acad Sci U S A (2012) 109:E1489–98.10.1073/pnas.120199410922573815
13. Voss-Andreae A Murphy JG Ellacott KL Stuart RC Nillni EA Cone RD et al. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology (2007) 148:1550–60.10.1210/en.2006-138917194736
14. Sohn JW Harris LE Berglund ED Liu T Vong L Lowell BB et al. Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. Cell (2013) 152:612–9.10.1016/j.cell.2012.12.02223374353
15. Shah BP Vong L Olson DP Koda S Krashes MJ Ye C et al. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc Natl Acad Sci U S A (2014) 111:13193–8.10.1073/pnas.140784311125157144
16. Garfield AS Li C Madara JC Shah BP Webber E Steger JS et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci (2015) 18:863–71.10.1038/nn.401125915476
17. Morgan DA Mcdaniel LN Yin T Khan M Jiang J Acevedo MR et al. Regulation of glucose tolerance and sympathetic activity by MC4R signaling in the lateral hypothalamus. Diabetes (2015) 64:1976–87.10.2337/db14-125725605803
18. Fan W Boston BA Kesterson RA Hruby VJ Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature (1997) 385:165–8.10.1038/385165a08990120
19. Huszar D Lynch CA Fairchild-Huntress V Dunmore JH Fang Q Berkemeier LR et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell (1997) 88:131–41.10.1016/S0092-8674(00)81865-69019399
20. Hinney A Schmidt A Nottebom K Heibult O Becker I Ziegler A et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab (1999) 84:1483–6.10.1210/jcem.84.4.572810199800
21. Farooqi IS Yeo GS Keogh JM Aminian S Jebb SA Butler G et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest (2000) 106:271–9.10.1172/JCI939710903343
22. Vaisse C Clement K Durand E Hercberg S Guy-Grand B Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest (2000) 106:253–62.10.1172/JCI923810903341
23. Bagnol D Lu XY Kaelin CB Day HE Ollmann M Gantz I et al. Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. J Neurosci (1999) 19:RC26.10479719
24. Haskell-Luevano C Chen P Li C Chang K Smith MS Cameron JL et al. Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. Endocrinology (1999) 140:1408–15.10.1210/en.140.3.140810067869
25. Wang D He X Zhao Z Feng Q Lin R Sun Y et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat (2015) 9:40.10.3389/fnana.2015.0004025870542
26. Joseph SA Pilcher WH Bennett-Clarke C. Immunocytochemical localization of ACTH perikarya in nucleus tractus solitarius: evidence for a second opiocortin neuronal system. Neurosci Lett (1983) 38:221–5.10.1016/0304-3940(83)90372-56314185
27. Schwartzberg DG Nakane PK. ACTH-related peptide containing neurons within the medulla oblongata of the rat. Brain Res (1983) 276:351–6.10.1016/0006-8993(83)90746-16313132
28. Palkovits M Mezey E Eskay RL. Pro-opiomelanocortin-derived peptides (ACTH/beta-endorphin/alpha-MSH) in brainstem baroreceptor areas of the rat. Brain Res (1987) 436:323–38.10.1016/0006-8993(87)91676-32829991
29. Cowley MA Smart JL Rubinstein M Cerdan MG Diano S Horvath TL et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature (2001) 411:480–4.10.1038/3507808511373681
30. Ciofi P Garret M Lapirot O Lafon P Loyens A Prevot V et al. Brain-endocrine interactions: a microvascular route in the mediobasal hypothalamus. Endocrinology (2009) 150:5509–19.10.1210/en.2009-058419837874
31. Langlet F Levin BE Luquet S Mazzone M Messina A Dunn-Meynell AA et al. Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab (2013) 17:607–17.10.1016/j.cmet.2013.03.00423562080
32. Schaeffer M Langlet F Lafont C Molino F Hodson DJ Roux T et al. Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc Natl Acad Sci U S A (2013) 110:1512–7.10.1073/pnas.121213711023297228
33. Balland E Dam J Langlet F Caron E Steculorum S Messina A et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab (2014) 19:293–301.10.1016/j.cmet.2013.12.01524506870
34. Blouet C Schwartz GJ. Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res (2010) 209:1–12.10.1016/j.bbr.2009.12.02420035790
35. Mountjoy KG. Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes. Biochem J (2010) 428:305–24.10.1042/BJ2009195720504281
36. Sohn JW Elmquist JK Williams KW. Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci (2013) 36:504–12.10.1016/j.tins.2013.05.00323790727
37. Baver SB Hope K Guyot S Bjorbaek C Kaczorowski C O’Connell KM. Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J Neurosci (2014) 34:5486–96.10.1523/JNEUROSCI.4861-12.201424741039
38. Elias CF Lee C Kelly J Aschkenasi C Ahima RS Couceyro PR et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron (1998) 21:1375–85.10.1016/S0896-6273(00)80656-X9883730
39. Ellacott KL Halatchev IG Cone RD. Characterization of leptin-responsive neurons in the caudal brainstem. Endocrinology (2006) 147:3190–5.10.1210/en.2005-087716601142
40. Khachaturian H Lewis ME Haber SN Akil H Watson SJ. Proopiomelanocortin peptide immunocytochemistry in rhesus monkey brain. Brain Res Bull (1984) 13:785–800.10.1016/0361-9230(84)90237-56099745
41. Betley JN Cao ZF Ritola KD Sternson SM. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell (2013) 155:1337–50.10.1016/j.cell.2013.11.00224315102
42. Broberger C Johansen J Johansson C Schalling M Hokfelt T. 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 (1998) 95:15043–8.10.1073/pnas.95.25.150439844012
43. Hahn TM Breininger JF Baskin DG Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci (1998) 1:271–2.10.1038/1082
44. Hentges ST Nishiyama M Overstreet LS Stenzel-Poore M Williams JT Low MJ. GABA release from proopiomelanocortin neurons. J Neurosci (2004) 24:1578–83.10.1523/JNEUROSCI.3952-03.200414973227
45. Meister B Gomuc B Suarez E Ishii Y Durr K Gillberg L. Hypothalamic proopiomelanocortin (POMC) neurons have a cholinergic phenotype. Eur J Neurosci (2006) 24:2731–40.10.1111/j.1460-9568.2006.05157.x17156199
46. Hentges ST Otero-Corchon V Pennock RL King CM Low MJ. Proopiomelanocortin expression in both GABA and glutamate neurons. J Neurosci (2009) 29:13684–90.10.1523/JNEUROSCI.3770-09.200919864580
47. Jarvie BC Hentges ST. Expression of GABAergic and glutamatergic phenotypic markers in hypothalamic proopiomelanocortin neurons. J Comp Neurol (2012) 520:3863–76.10.1002/cne.2312722522889
48. Wittmann G Hrabovszky E Lechan RM. Distinct glutamatergic and GABAergic subsets of hypothalamic pro-opiomelanocortin neurons revealed by in situ hybridization in male rats and mice. J Comp Neurol (2013) 521:3287–302.10.1002/cne.2335023640796
49. Mercer AJ Hentges ST Meshul CK Low MJ. Unraveling the central proopiomelanocortin neural circuits. Front Neurosci (2013) 7:19.10.3389/fnins.2013.0001923440036
50. Balthasar N Dalgaard LT Lee CE Yu J Funahashi H Williams T et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell (2005) 123:493–505.10.1016/j.cell.2005.08.03516269339
51. Rossi J Balthasar N Olson D Scott M Berglund E Lee CE et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab (2011) 13:195–204.10.1016/j.cmet.2011.01.01021284986
52. Morton GJ Cummings DE Baskin DG Barsh GS Schwartz MW. Central nervous system control of food intake and body weight. Nature (2006) 443:289–95.10.1038/nature0502616988703
53. Luquet S Perez FA Hnasko TS Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science (2005) 310:683–5.10.1126/science.111552416254186
54. Wu Q Howell MP Cowley MA Palmiter RD. Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc Natl Acad Sci U S A (2008) 105:2687–92.10.1073/pnas.071206210518272480
55. Wu Q Boyle MP Palmiter RD. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell (2009) 137:1225–34.10.1016/j.cell.2009.04.02219563755
56. Aponte Y Atasoy D Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci (2011) 14:351–5.10.1038/nn.273921209617
57. Krashes MJ Koda S Ye C Rogan SC Adams AC Cusher DS et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest (2011) 121:1424–8.10.1172/JCI4622921364278
58. Atasoy D Betley JN Su HH Sternson SM. Deconstruction of a neural circuit for hunger. Nature (2012) 488:172–7.10.1038/nature1127022801496
59. Krashes MJ Shah BP Koda S Lowell BB. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab (2013) 18:588–95.10.1016/j.cmet.2013.09.00924093681
60. Zhan C Zhou J Feng Q Zhang JE Lin S Bao J et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J Neurosci (2013) 33:3624–32.10.1523/JNEUROSCI.2742-12.201323426689
61. Betley JN Xu S Cao ZF Gong R Magnus CJ Yu Y et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature (2015) 521:180–5.10.1038/nature1441625915020
62. Carter ME Soden ME Zweifel LS Palmiter RD. Genetic identification of a neural circuit that suppresses appetite. Nature (2013) 503:111–4.10.1038/nature1259624121436
63. Dietrich MO Bober J Ferreira JG Tellez LA Mineur YS Souza DO et al. AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors. Nat Neurosci (2012) 15:1108–10.10.1038/nn.314722729177
64. Chen Y Lin YC Kuo TW Knight ZA. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell (2015) 160:829–41.10.1016/j.cell.2015.01.03325703096
65. Barth C Villringer A Sacher J. Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci (2015) 9:37.10.3389/fnins.2015.0003725750611
66. Ebling FJ. Hypothalamic control of seasonal changes in food intake and body weight. Front Neuroendocrinol (2015) 37:97–107.10.1016/j.yfrne.2014.10.00325449796
67. Chapman DB Theodosis DT Montagnese C Poulain DA Morris JF. Osmotic stimulation causes structural plasticity of neurone-glia relationships of the oxytocin but not vasopressin secreting neurones in the hypothalamic supraoptic nucleus. Neuroscience (1986) 17:679–86.10.1016/0306-4522(86)90039-42422593
68. Theodosis DT Montagnese C Rodriguez F Vincent JD Poulain DA. Oxytocin induces morphological plasticity in the adult hypothalamo-neurohypophysial system. Nature (1986) 322:738–40.10.1038/322738a03748154
69. Garcia-Segura LM Baetens D Naftolin F. Synaptic remodelling in arcuate nucleus after injection of estradiol valerate in adult female rats. Brain Res (1986) 366:131–6.10.1016/0006-8993(86)91287-43697673
70. Olmos G Naftolin F Perez J Tranque PA Garcia-Segura LM. Synaptic remodeling in the rat arcuate nucleus during the estrous cycle. Neuroscience (1989) 32:663–7.10.1016/0306-4522(89)90288-12601838
71. Naftolin F Garcia-Segura LM Horvath TL Zsarnovszky A Demir N Fadiel A et al. Estrogen-induced hypothalamic synaptic plasticity and pituitary sensitization in the control of the estrogen-induced gonadotrophin surge. Reprod Sci (2007) 14:101–16.10.1177/193371910730105917636222
72. Dietrich MO Horvath TL. Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci (2013) 36:65–73.10.1016/j.tins.2012.12.00523318157
73. Pinto S Roseberry AG Liu H Diano S Shanabrough M Cai X et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science (2004) 304:110–5.10.1126/science.108945915064421
74. Gao Q Mezei G Nie Y Rao Y Choi CS Bechmann I et al. Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med (2007) 13:89–94.10.1038/nm152517195839
75. Gyengesi E Liu ZW D’Agostino G Gan G Horvath TL Gao XB et al. Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. Endocrinology (2010) 151:5395–402.10.1210/en.2010-068120843996
76. Andrews ZB Liu ZW Walllingford N Erion DM Borok E Friedman JM et al. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature (2008) 454:846–51.10.1038/nature0718118668043
77. Vong L Ye C Yang Z Choi B Chua S Jr Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron (2011) 71:142–54.10.1016/j.neuron.2011.05.02821745644
78. Yang Y Atasoy D Su HH Sternson SM. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell (2011) 146:992–1003.10.1016/j.cell.2011.07.03921925320
79. Liu T Kong D Shah BP Ye C Koda S Saunders A et al. Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron (2012) 73:511–22.10.1016/j.neuron.2011.11.02722325203
80. Tschop M Smiley DL Heiman ML. Ghrelin induces adiposity in rodents. Nature (2000) 407:908–13.10.1038/3503809011057670
81. Tong Q Ye CP Jones JE Elmquist JK Lowell BB. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci (2008) 11:998–1000.10.1038/nn.216719160495
82. Benani A Hryhorczuk C Gouaze A Fioramonti X Brenachot X Guissard C et al. Food intake adaptation to dietary fat involves PSA-dependent rewiring of the arcuate melanocortin system in mice. J Neurosci (2012) 32:11970–9.10.1523/JNEUROSCI.0624-12.201222933782
83. Volterra A Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci (2005) 6:626–40.10.1038/nrn172216025096
84. Garcia-Caceres C Fuente-Martin E Argente J Chowen JA. Emerging role of glial cells in the control of body weight. Mol Metab (2012) 1:37–46.10.1016/j.molmet.2012.07.001
85. Buckman LB Ellacott KL. The contribution of hypothalamic macroglia to the regulation of energy homeostasis. Front Syst Neurosci (2014) 8:212.10.3389/fnsys.2014.0021225374514
86. Argente-Arizon P Freire-Regatillo A Argente J Chowen JA. Role of non-neuronal cells in body weight and appetite control. Front Endocrinol (2015) 6:42.10.3389/fendo.2015.0004225859240
87. Teschemacher AG Gourine AV Kasparov S. A role for astrocytes in sensing the brain microenvironment and neuro-metabolic integration. Neurochem Res (2015).10.1007/s11064-015-1562-9
88. Kum W Cockram CS Zhu SQ Teoh R Vallance-Owen J Young JD. Insulin binding and effects on pyrimidine nucleoside uptake and incorporation in cultured mouse astrocytes. J Neurochem (1987) 49:1293–300.10.1111/j.1471-4159.1987.tb10023.x3305789
89. Vielkind U Walencewicz A Levine JM Bohn MC. Type II glucocorticoid receptors are expressed in oligodendrocytes and astrocytes. J Neurosci Res (1990) 27:360–73.10.1002/jnr.4902703152097380
90. Vannucci SJ Maher F Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia (1997) 21:2–21.10.1002/(SICI)1098-1136(199709)21:1<2::AID-GLIA2>3.0.CO;2-C9298843
91. Cardona-Gomez GP Chowen JA Garcia-Segura LM. Estradiol and progesterone regulate the expression of insulin-like growth factor-I receptor and insulin-like growth factor binding protein-2 in the hypothalamus of adult female rats. J Neurobiol (2000) 43:269–81.10.1002/(SICI)1097-4695(20000605)43:3<269::AID-NEU5>3.0.CO;2-D10842239
92. Cardona-Gomez GP Doncarlos L Garcia-Segura LM. Insulin-like growth factor I receptors and estrogen receptors colocalize in female rat brain. Neuroscience (2000) 99:751–60.10.1016/S0306-4522(00)00228-110974438
93. Cheunsuang O Morris R. Astrocytes in the arcuate nucleus and median eminence that take up a fluorescent dye from the circulation express leptin receptors and neuropeptide Y Y1 receptors. Glia (2005) 52:228–33.10.1002/glia.2023915968634
94. Hsuchou H He Y Kastin AJ Tu H Markadakis EN Rogers RC et al. Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain (2009) 132:889–902.10.1093/brain/awp02919293246
95. Hsuchou H Pan W Barnes MJ Kastin AJ. Leptin receptor mRNA in rat brain astrocytes. Peptides (2009) 30:2275–80.10.1016/j.peptides.2009.08.02319747514
96. Kim JG Suyama S Koch M Jin S Argente-Arizon P Argente J et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci (2014) 17:908–10.10.1038/nn.372524880214
97. Guillod-Maximin E Lorsignol A Alquier T Penicaud 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) 16:464–71.10.1111/j.1365-2826.2004.01185.x15117340
98. Marty N Dallaporta M Foretz M Emery M Tarussio D Bady I et al. Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. J Clin Invest (2005) 115:3545–53.10.1172/JCI2630916322792
99. McDougal DH Hermann GE Rogers RC. Astrocytes in the nucleus of the solitary tract are activated by low glucose or glucoprivation: evidence for glial involvement in glucose homeostasis. Front Neurosci (2013) 7:249.10.3389/fnins.2013.0024924391532
100. McDougal DH Viard E Hermann GE Rogers RC. Astrocytes in the hindbrain detect glucoprivation and regulate gastric motility. Auton Neurosci (2013) 175:61–9.10.1016/j.autneu.2012.12.00623313342
101. Fuente-Martin E Garcia-Caceres C Granado M De Ceballos ML Sanchez-Garrido MA Sarman B et al. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J Clin Invest (2012) 122:3900–13.10.1172/JCI6410223064363
102. Buckman LB Thompson MM Lippert RN Blackwell TS Yull FE Ellacott KL. Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. Mol Metab (2015) 4:58–63.10.1016/j.molmet.2014.10.00125685690
103. Araque A Parpura V Sanzgiri RP Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci (1999) 22:208–15.10.1016/S0166-2236(98)01349-610322493
104. Araque A Carmignoto G Haydon PG Oliet SH Robitaille R Volterra A. Gliotransmitters travel in time and space. Neuron (2014) 81:728–39.10.1016/j.neuron.2014.02.00724559669
105. Haam J Halmos KC Di S Tasker JG. Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits. J Neurosci (2014) 34:6201–13.10.1523/JNEUROSCI.3178-13.201424790191
106. Yang L Qi Y Yang Y. Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Rep (2015) 11:798–807.10.1016/j.celrep.2015.04.00225921535
107. Shen L Tso P Woods SC Clegg DJ Barber KL Carey K et al. Brain apolipoprotein E: an important regulator of food intake in rats. Diabetes (2008) 57:2092–8.10.2337/db08-029118559657
108. Oliet SH Piet R Poulain DA. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science (2001) 292:923–6.10.1126/science.105916211340204
109. Oliet SH. Functional consequences of morphological neuroglial changes in the magnocellular nuclei of the hypothalamus. J Neuroendocrinol (2002) 14:241–6.10.1046/j.0007-1331.2001.00766.x11999725
110. Theodosis DT Poulain DA Oliet SH. Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol Rev (2008) 88:983–1008.10.1152/physrev.00036.200718626065
111. Bernardinelli Y Randall J Janett E Nikonenko I Konig S Jones EV et al. Activity-dependent structural plasticity of perisynaptic astrocytic domains promotes excitatory synapse stability. Curr Biol (2014) 24:1679–88.10.1016/j.cub.2014.06.02525042585
112. Garcia-Caceres C Fuente-Martin E Burgos-Ramos E Granado M Frago LM Barrios V et al. Differential acute and chronic effects of leptin on hypothalamic astrocyte morphology and synaptic protein levels. Endocrinology (2011) 152:1809–18.10.1210/en.2010-125221343257
113. Horvath TL Sarman B Garcia-Caceres C Enriori PJ Sotonyi P Shanabrough M et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci U S A (2010) 107:14875–80.10.1073/pnas.100428210720679202
114. Gouaze A Brenachot X Rigault C Krezymon A Rauch C Nedelec E et al. Cerebral cell renewal in adult mice controls the onset of obesity. PLoS One (2013) 8:e72029.10.1371/journal.pone.007202923967273
115. Ziotopoulou M Mantzoros CS Hileman SM Flier JS. Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. Am J Physiol Endocrinol Metab (2000) 279:E838–45.11001766
116. Koch M Varela L Kim JG Kim JD Hernandez-Nuno F Simonds SE et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature (2015) 519:45–50.10.1038/nature1426025707796
117. Labouebe G Liu S Dias C Zou H Wong JC Karunakaran S et al. Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat Neurosci (2013) 16:300–8.10.1038/nn.332123354329
118. Baroncini M Jissendi P Catteau-Jonard S Dewailly D Pruvo JP Francke JP et al. Sex steroid hormones-related structural plasticity in the human hypothalamus. Neuroimage (2010) 50:428–33.10.1016/j.neuroimage.2009.11.07419969095
119. Locke AE Kahali B Berndt SI Justice AE Pers TH Day FR et al. Genetic studies of body mass index yield new insights for obesity biology. Nature (2015) 518:197–206.10.1038/nature1417725673413