Central leptin and ghrelin signalling: Comparing and contrasting their mechanisms of action in the brain

Reviews in Endocrine and Metabolic Disorders

Volumn 12, Issue 3, 2011, Pages 197-209

  Shan, Xiaoye ^a   Yeo, Giles S H ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

CNS; Food intake; Ghrelin; Leptin

Indexed keywords

G PROTEIN COUPLED RECEPTOR; GHRELIN; GHRELIN RECEPTOR; LEPTIN; LEPTIN RECEPTOR; STAT3 PROTEIN;

ARTICLE; BRAIN FUNCTION; BRAIN REGION; ELECTROPHYSIOLOGY; FOOD INTAKE; GENETIC TRANSCRIPTION; HUMAN; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; HYPOTHALAMUS; HYPOTHALAMUS VENTROMEDIAL NUCLEUS; NERVE CELL PLASTICITY; OBESITY;

ANIMALS; BRAIN; EATING; ENERGY METABOLISM; GHRELIN; HOMEOSTASIS; HUMANS; LEPTIN; RECEPTORS, GHRELIN; RECEPTORS, LEPTIN; SIGNAL TRANSDUCTION;

EID: 80054848915     PISSN: 13899155     EISSN: 15732606     Source Type: Journal    
DOI: 10.1007/s11154-011-9171-7     Document Type: Article

References (145)

1. Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homolog. Nature. 1994;372:425-32. (Pubitemid 24365442)
2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-60. (Pubitemid 129516334)
3. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive leptin concen-trations in normal-weight and obese humans. N Engl J Med. 1996;334:292-5. (Pubitemid 26033933)
4. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763-70. (Pubitemid 28485436)
5. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250-2. (Pubitemid 26251358)
6. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908-13.
7. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA. 2008;105:6320-5. (Pubitemid 351758344)
8. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387-96. (Pubitemid 351192001)
9. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating Ghrelin levels are decreased in human obesity. Diabetes. 2001;50:707-9. (Pubitemid 32242624)
10. Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, et al. Elevated plasma ghrelin levels in Prader-Willi syndrome. Nat Med. 2002;8:643-4. (Pubitemid 34778697)
11. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714-9. (Pubitemid 33641587)
12. Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R, et al. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Investig. 2001;24:Rc19-21. (Pubitemid 32573786)
13. Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, et al. GOAT links dietary lipids with the endocrine control ofenergy balance. Nat Med. 2009;15:741-5.
14. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology. 2000;141:4325-8.
15. Ashby DR, Ford HE, Wynne KJ, Wren AM, Murphy KG, Busbridge M, et al. Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int. 2009;76:199-206.
16. Druce MR, Neary NM, Small CJ, Milton J, Monteiro M, Patterson M, et al. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. Int J Obes. 2006;30:293-6. (Pubitemid 43237685)
17. Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, et al. Ghrelin increases food intake in obese as well as lean subjects. Int J Obes. 2005;29:1130-6. (Pubitemid 41192222)
18. Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C, et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2004;89:2832-6. (Pubitemid 38766373)
19. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263-71. (Pubitemid 26007816)
20. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, et al. Anatomic localization ofalternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA. 1997;94:7001-5. (Pubitemid 27281980)
21. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AWK, Wang YP, et al. STAT3 signalling is required for leptin regulation ofenergy balance but not reproduction. Nature. 2003;421:856-9. (Pubitemid 36254146)
22. Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem. 1997;272:32686-95. (Pubitemid 28011961)
23. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG, Schwartz MW. Intracellular signalling-key enzyme in leptin-induced anorexia. Nature. 2001;413:794-5. (Pubitemid 33026839)
24. Depoortere I. Targeting the ghrelin receptor to regulate food intake. Regul Pept. 2009;156:13-23.
25. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273:974-7. (Pubitemid 26275178)
26. Lopez M, Lage R, Saha AK, Perez-Tilve D, Vazquez MJ, Varela L, et al. Hypothalamic fatty acid metabolism mediates the orexigenic action ofghrelin. Cell Metab. 2008;7:389-99. (Pubitemid 351618114)
27. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8:571-8. (Pubitemid 40594196)
28. Oswal A, Yeo GSH. Appetite regulatory peptides-the leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics. Obes Rev. 2007;8:293-306. (Pubitemid 46944499)
29. Bertagna X. Proopiomelanocortin-derived peptides. Endocrinol Metab Clin North Am. 1994;23:467-85. (Pubitemid 24300121)
30. Castro MG, Morrison E. Post-translational processing of proo-piomelanocortin in the pituitary and in the brain. Crit Rev Neurobiol. 1997;11:35-57. (Pubitemid 27165970)
31. Challis BG, Coll AP, Yeo GS, Pinnock SB, Dickson SL, Thresher RR, et al. Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects ofpeptide-YY(3-36). Proc Natl Acad Sci USA. 2004;101:4695-700. (Pubitemid 38437473)
32. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19:155-7. (Pubitemid 28248796)
33. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, et al. Targeted disruption of the melanocortin-4 receptorresults in obesity in mice. Cell. 1997;88:131-41. (Pubitemid 27180337)
34. Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity Nat Genet. 1998;20:113-4. (Pubitemid 28455439)
35. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity Nat Genet. 1998;20:111-2. (Pubitemid 28455438)
36. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085-95. (Pubitemid 36337319)
37. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z,etal. Post-embryonic ablation of Ag RP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 2005;19:1680-2. (Pubitemid 41429528)
38. Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, et al. Agouti-related peptide-expressing neurons are mandato-ry for feeding. Nat Neurosci. 2005;8:1289-91. (Pubitemid 41630413)
39. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/Ag RP neurons are essential for feeding in adult mice but can be ablated inneonates. Science. 2005;310:683-5. (Pubitemid 41528162)
40. Xu AW, Kaelin CB, Morton GJ, Ogimoto K, Stanhope K, Graham J, et al. Effects of hypothalamic neurodegeneration on energy balance. PLo S Biol. 2005;3:e415.
41. Cowley MA, Smart JL, Rubinstein M, Cordan 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. (Pubitemid 32494394)
42. Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK. Expression of melanocortin 4 receptor m RNA in the central nervous system of the rat J Comp Neurol. 2003;457:213-35. (Pubitemid 36158283)
43. Liu HY, Kishi T, Roseberry AG, Cai XL, 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. (Pubitemid 36975878)
44. Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997;138:4489-92. (Pubitemid 27408500)
45. Wilson BD, Bagnol D, Kaelin CB, Ollmann MM, Gantz I, Watson SJ, et al. Physiological and anatomical circuitry between Agouti-related protein and leptin signaling. Endocrinology. 1999;140:2387-97. (Pubitemid 30636480)
46. Guan XM, Yu H, Palyha OC, Mc Kee KK, Feighner SD, Sirinathsinghji DJS, et al. Distribution of m RNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Mol Brain Res. 1997;48:23-9. (Pubitemid 27298124)
47. Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S. Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology 2002;143:3268-75. (Pubitemid 34925701)
48. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-8. (Pubitemid 32144284)
49. Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropep-tide Y/Y1 receptorpathway. Diabetes. 2001;50:227-32. (Pubitemid 32127276)
50. Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 2004;145:2607-12. (Pubitemid 38686204)
51. Brown LM, Benoit SC, Woods SC, Clegg DJ. Intraventricular (i3vt) ghrelin increases food intake in fatty Zucker rats. Peptides. 2007;28:612-6. (Pubitemid 46205010)
52. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C,etal. Leptin differentially regulates NPYand POMC neurons projecting to the lateral hypothalamic area. Neuron. 1999;23:775-86. (Pubitemid 29411566)
53. Ahima RS, Kelly J, Elmquist JK, Flier JS. Distinct physiologic and neuronal responses to decreased leptin and mild hyper-leptinemia. Endocrinology 1999;140:4923-31.
54. Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, et al. Leptin increases hypothalamic pro-opiomelanocortin m RNA expression in the rostral arcuate nucleus. Diabetes. 1997;46:2119-23. (Pubitemid 27512108)
55. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expres-sion. Endocrinology 2000;141:4797-800. (Pubitemid 32055162)
56. Goto M, Arima H, Watanabe M, Hayashi M, Banno R, Sato I, et al. Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures. Endocrinology. 2006;147:5102-9. (Pubitemid 44790562)
57. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003;37:649-61. (Pubitemid 36262986)
58. Wang JH, Wang F, Yang MJ, Yu DF, Wu WN, Liu J, et al. Leptin regulated calcium channels of neuropeptide Y and proopiomela-nocortin neurons by activation of different signal pathways. Neuroscience. 2008;156:89-98.
59. Plum L, Ma XS, Hampel B, Balthasar N, Coppari R, Munzberg H, et al. Enhanced PIP3 signaling in POMC neurons causes K-ATP channel activation and leads to diet-sensitive obesity. J Clin Investig. 2006;116:1886-901. (Pubitemid 44033313)
60. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/Ag RP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci. 2004;7:493-4. (Pubitemid 38544585)
61. Pinto S, Roseberry AG, Liu HY, Diano S, Shanabrough M, Cai XL, et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science. 2004;304:110-5. (Pubitemid 38451468)
62. Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest. 2006;116:3229-39. (Pubitemid 44878637)
63. 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. (Pubitemid 41546678)
64. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor m RNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 1996;387:113-6.
65. Qi Y, Henry BA, Oldfield BJ, Clarke IJ. The action of leptin on appetite-regulating cells in the ovine hypothalamus: demonstra-tion of direct action in the absence of the arcuate nucleus. Endocrinology. 2010;151:2106-16.
66. Olszewski PK, Grace MK, Billington CJ, Levine AS. Hypotha-lamic paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity. Peptides. 2003;24:919-23. (Pubitemid 37011440)
67. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 2001;50:2540-7. (Pubitemid 33642772)
68. Tung YCL, Ma M, Piper S, Coll A, O'Rahilly S, Yeo GSH. Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus. J Neurosci. 2008;28:12419-26.
69. Piper M, Holt C. RNA translation in axons. Annu Rev Cell Dev Biol. 2004;20:505-23. (Pubitemid 39488648)
70. Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ, Saper CB, et al. Chemical characterization ofleptin-activated neurons in the rat brain. J Comp Neurol. 2000;423:261-81. (Pubitemid 30421790)
71. Munzberg H, Huo LH, Nillni EA, Hollenberg AN, Bjorbaek C. Role of signal transducer and activator of transcription 3 in regulation ofhypothalamic proopiomelanocortin gene expression by leptin. Endocrinology. 2003;144:2121-31. (Pubitemid 36543352)
72. Dhillon H, Zigman JM, Ye CP, Lee CE, Mc Govern RA, Tang VS, et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron. 2006;49:191-203. (Pubitemid 43089637)
73. Bingham NC, Anderson KK, Reuter AL, Stallings NR, Parker KL. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 2008;149:2138-48. (Pubitemid 351574486)
74. Zhang R, Dhillon H, Yin H, Yoshimura A, Lowell BB, Maratos-Flier E, et al. Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight. Endocrinology. 2008;149:5654-61.
75. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Expression of ghrelin receptor m RNA in the rat and the mouse brain. J Comp Neurol. 2006;494:528-48. (Pubitemid 41791000)
76. Lawrence CB, Snape AC, Baudoin FMH, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology. 2002;143:155-62. (Pubitemid 34056414)
77. Kim MS, Yoon CY, Park KH, Shin CS, Park KS, Kim SY, et al. Changes in ghrelin and ghrelin receptor expression according to feeding status. Neuro Report. 2003;14:1317-20.
78. Nogueiras R, Tovar S, Mitchell SE, Rayner DV, Archer ZA, Dieguez C, et al. Regulation of growth hormone secretagogue receptor gene expression in the arcuate nuclei of the rat by leptin and ghrelin. Diabetes. 2004;53:2552-8. (Pubitemid 39299261)
79. Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T. Hypocretin/ orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and Agouti gene-related protein systems. J Comp Neurol. 1998;402:460-74. (Pubitemid 29001075)
80. Horvath TL, Diano S, van den Pol AN. Synaptic interaction between hypocretin (Orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic andendocrineregulations. JNeurosci. 1999;19:1072-87. (Pubitemid 29066169)
81. Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci. 1998;18:559-72. (Pubitemid 28046812)
82. Hakansson ML, de Lecea L, Sutcliffe JG, Yanagisawa M, Meister B. Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus. J Neuroendocrinol. 1999;11:653-63. (Pubitemid 29338682)
83. Horvath TL, Gao XB. Input organization and plasticity of hypocretin neurons: possible clues to obesity's association with insomnia. Cell Metab. 2005;1:279-86. (Pubitemid 43960609)
84. Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, Shimbara T, et al. Ghrelin-induced food intake is mediated via the orexin pathway Endocrinology. 2003;144:1506-12. (Pubitemid 36428493)
85. Alon T, Friedman JM. Late-onset leanness in mice with targeted ablation of melanin concentrating hormone neurons. J Neurosci. 2006;26:389-97. (Pubitemid 43237101)
86. Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature. 1998;396:670-4.
87. Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J, et al. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Investig. 2001;107:379-86. (Pubitemid 32157970)
88. Qu DQ, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature. 1996;380:243-7. (Pubitemid 26090645)
89. Rossi M, Choi SJ, OShea D, Miyoshi T, Ghatei MA, Bloom SR. Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology. 1997;138:351-5. (Pubitemid 27009443)
90. Stricker-Krongrad A, Dimitrov T, Beck B. Central and peripheral dysregulation of melanin-concentrating hormone in obese Zucker rats. Mol Brain Res. 2001;92:43-8. (Pubitemid 32718703)
91. Sahu A. Leptin decreases food intake induced by melanin-concentrating hormone (MCH), galanin (GAL) and neuropeptide Y (NPY) in the rat Endocrinology 1998;139:4739-42. (Pubitemid 28487794)
92. Grill HJ. Distributedneural control ofenergy balance: contributions fromhindbrain andhypothalamus. Obesity 2006;14:216-21.
93. Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin DG. Evidence that the caudal brainstem is a target for the inhibitory effect ofleptin on food intake. Endocrinology. 2002;143:239-46. (Pubitemid 34056425)
94. Mercer JG, Moar KM, Findlay PA, Hoggard N, Adam CL. Association of leptin receptor (OB-Rb), NPY and GLP-1 gene expression in the ovine and murine brainstem. Regul Pept. 1998;75-6:271-8. (Pubitemid 28477537)
95. Williams DL, Baskin DG, Schwartz MW. Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin. Am J Physiol Regul Integr Comp Physiol. 2009;297:R1238-46.
96. Barrachina MD, Martinez V, Wang LX, Wei JY, Tache Y. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci USA. 1997;94:10455-60. (Pubitemid 27407063)
97. Emond M, Schwartz GJ, Ladenheim EE, Moran TH. Central leptin modulates behavioral and neural responsivity to CCK. Am J Physiol Regul Integr Comp Physiol. 1999;276:R1545-9. (Pubitemid 29249682)
98. Mc Minn JE, Sindelar DK, Havel PJ, Schwartz MW. Leptin deficiency induced by fasting impairs the satiety response to cholecystokinin. Endocrinology. 2000;141:4442-8. (Pubitemid 32055119)
99. Morton GJ, Blevins JE, Williams DL, Niswender KD, Gelling RW, Rhodes C J, et al. Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Investig. 2005;115:703-10. (Pubitemid 40322245)
100. Date Y, Toshinai K, Koda S, Miyazato M, Shimbara T, Tsuruta T, et al. Peripheral interaction of ghrelin with cholecystokinin on feeding regulation. Endocrinology. 2005;146:3518-25. (Pubitemid 41058123)
101. Chelikani PK, Haver AC, Reidelberger RD. Ghrelin attenuates the inhibitory effects ofglucagon-like peptide-1 and peptide YY (3-36) on food intake and gastric emptying in rats. Diabetes. 2006;55:3038-46. (Pubitemid 44923640)
102. Unniappan S, Kieffer TJ. Leptin extends the anorectic effects of chronic PYY(3-36) administration in ad libitum-fed rats. Am J Physiol Regul Integr Comp Physiol. 2008;295:R51-8.
103. Williams DL, Baskin DG, Schwartz MW. Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes. 2006;55:3387-93. (Pubitemid 44923597)
104. Hosoi T, Kawagishi T, Okuma Y, Tanaka J, Nomura Y. Brain stem is a direct target for leptin's action in the central nervous system. Endocrinology. 2002;143:3498-504. (Pubitemid 34925724)
105. Ellacott KL, Halatchev IG, Cone RD. Characterization ofleptin-responsive neurons in the caudal brainstem. Endocrinology 2006;147:3190-5. (Pubitemid 43901109)
106. Huo LH, Grill HJ, Bjorbaek C. Divergent regulation of proopiomelanocortin neurons by leptin in the nucleus of the solitary tract and in the arcuate hypothalamic nucleus. Diabetes. 2006;55:567-73. (Pubitemid 43343211)
107. Faulconbridge LF, Grill HJ, Kaplan JM, Daniels D. Caudal brainstem delivery of ghrelin induces fos expression in the-nucleus of the solitary tract, but not in the arcuate or paraventricular nuclei of the hypothalamus. Brain Res. 2008;1218:151-7.
108. Berridge KC. The debate over dopamine's role in reward: the case forincentive salience. Psychopharmacology. 2007;191:391-431. (Pubitemid 46355895)
109. Schultz W. Behavioral dopamine signals. Trends Neurosci. 2007;30:203-10. (Pubitemid 46654238)
110. Wise RA. Dopamine, learning and motivation. Nat Rev Neuro-sci. 2004;5:483-94. (Pubitemid 38715515)
111. Wise RA. Role of brain dopamine in food reward and reinforce-ment. Philos Trans R Soc Lond B Biol Sci. 2006;361:1149-58. (Pubitemid 44874226)
112. Wise RA, Spindler J, Dewit H, Gerber GJ. Neuroleptic-induced anhedonia in rats-pimozide blocks reward quality of food. Science. 1978;201:262-4. (Pubitemid 8396751)
113. Farooqi IS, Bullmore E, Keogh J, Gillard J, O'Rahilly S, Fletcher PC Leptin regulates striatal regions and human eating. Behav Sci. 2007;317:1355-5.
114. Malik S, Mc Glone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive behavior Cell Metab. 2008;7:400-9. (Pubitemid 351598026)
115. Figlewicz DP, Evans SB, Murphy J, Hoen M, Baskin DG. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res. 2003;964:107-15. (Pubitemid 36165075)
116. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron. 2006;51:801-10. (Pubitemid 44374908)
117. Jiang H, Betancourt L, Smith RG. Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 hetero-dimers. Mol Endocrinol. 2006;20:1772-85. (Pubitemid 44148083)
118. Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA. Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addict Biol. 2007;12:6-16. (Pubitemid 46405994)
119. Naleid AM, Grace MK, Cummings DE, Levine AS. Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides. 2005;26:2274-9. (Pubitemid 41584095)
120. Kim KS, Yoon YR, Lee HJ, Yoon S, Kim SY, Shin SW, et al. Enhanced hypothalamic leptin signaling in mice lacking dopa-mine D-2 receptors. J Biol Chem. 2010;285:8905-17.
121. Krugel U, Schraft T, Kittner H, Kiess W, Illes P. Basal and feeding-evoked dopamine release in the rat nucleus accumbens is depressed by leptin. Eur J Pharmacol. 2003;482:185-7. (Pubitemid 37505943)
122. Perry ML, Leinninger GM, Chen R, Luderman KD, Yang H, Gnegy ME, et al. Leptin promotes dopamine transporter and tyrosine hydroxylase activity in the nucleus accumbens of Sprague-Dawley rats. J Neurochem. 2010.
123. Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA. Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addict Biol. 2006;11:45-54. (Pubitemid 46696736)
124. Di Chiara G, Bassareo V. Reward system and addiction: what dopamine does and doesn't do (vol 7, pg 69, 2007). Curr Opin Pharmacol. 2007;7:233-3.
125. Volkow ND, Fowler JS, Wang GJ. Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol. 2002;13:355-66. (Pubitemid 35178832)
126. Davis C, Carter JC. Compulsive overeating as an addiction disorder. Areview of theory andevidence. Appetite. 2009;53:1-8.
127. Fadel J, Deutch AY Anatomical substrates of orexin-dopamine interactions: Lateral hypothalamic projections to the ventral tegmental area. Neuroscience. 2002;111:379-87. (Pubitemid 34442621)
128. Mogenson GJ, Swanson LW, Wu M. Neural projections from nucleus accumbens to globus pallidus, substantia innominata, and lateral preoptic-lateral hypothalamic area-an anatomical and electro-physiological investigation in the rat. J Neurosci. 1983;3:189-202. (Pubitemid 13193402)
129. Di Leone RJ, Georgescu D, Nestler EJ. Lateral hypothalamic neuro-peptides in reward and drug addiction. Life Sci. 2003;73:759-68. (Pubitemid 36703270)
130. 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. 2006;49:589-601. (Pubitemid 43221893)
131. Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang HY, Barrera JG, et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. 2009;10:89-98.
132. Squire LR. Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem. 2004;82:171-7. (Pubitemid 39298714)
133. Molteni R, Barnard RJ, Ying Z, Roberts CK, Gomez-Pinilla F. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neurosci-ence. 2002;112:803-14. (Pubitemid 34667045)
134. Martin B, Pearson M, Brenneman R, Golden E, Keselman A, Iyun T, et al. Conserved and differential effects ofdietary energy intake on the hippocampal transcriptomes offemales and males. Plos One. 2008;3.
135. Tracy AL, Jarrard LE, Davidson TL. The hippocampus and motivation revisited: appetite and activity Behav Brain Res. 2001;127:13-23. (Pubitemid 33062401)
136. Diano S, Farr SA, Benoit SC, Mc Nay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006;9:381-8. (Pubitemid 43290968)
137. Lathe R. Hormones and the hippocampus. J Endocrinol. 2001;169:205-31. (Pubitemid 32447603)
138. Moon M, Kim S, Hwang L, Park S. Ghrelin regulates hippocam-pal neurogenesis in adult mice. Endocr J. 2009;56:525-31.
139. Ur E, Wilkinson DA, Morash BA, Wilkinson M. Leptin immunoreactivity is localized to neurons in rat brain. Neuroen-docrinology. 2002;75:264-72. (Pubitemid 34455100)
140. Shanley LJ, Irving AJ, Harvey J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosci. 2001;21: art. no.-RC186.
141. Durakoglugil M, Irving AJ, Harvey J. Leptin induces a novel form of NMDA receptor-dependent long-term depression. J Neurochem. 2005;95:396-405. (Pubitemid 41457508)
142. Moult PR, Milojkovic B, Harvey J. Leptin reverses long-term potentiation at hippocampal CA1 synapses. J Neurochem. 2009;108:685-96.
143. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience. 2002;113:607-15. (Pubitemid 34874684)
144. Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun. 2004;313:635-41. (Pubitemid 38021878)
145. Kitamura T, Feng Y, Kitamura YI, Chua Jr SC, Xu AW, Barsh GS, et al. Forkhead protein Fox O1 mediates Agrp-dependent effects of leptin on food intake. Nat Med. 2006;12:534-40.