Interaction between energy homeostasis and reproduction: Central effects of leptin and ghrelin on the reproductive axis

Hormone and Metabolic Research

Volumn 45, Issue 13, 2013, Pages 919-927

  Tena Sempere, M ^a,b  

^a UNIVERSITY OF CÓRDOBA   (Spain)

^b INSTITUTO DE SALUD CARLOS III   (Spain)

Author keywords

fertility; gonadotropin; leptin; neuropeptides

Indexed keywords

AGOUTI RELATED PROTEIN; COCAINE AND AMPHETAMINE REGULATED TRANSCRIPT PEPTIDE; CORTICOTROPIN RELEASING FACTOR; ENZYME; ESTRADIOL; ESTROGEN RECEPTOR ALPHA; FOLLITROPIN; GHRELIN; GHRELIN O ACYLTRANSFERASE; GHRELIN RECEPTOR; GONADORELIN; GONADOTROPIN; INSULIN; INSULIN RECEPTOR; KISSPEPTIN; KISSPEPTIN 10; LEPTIN; LEPTIN RECEPTOR; LEUCINE; LUTEINIZING HORMONE; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; NALOXONE; NEUROPEPTIDE Y; NITRIC OXIDE; PROOPIOMELANOCORTIN; RAPAMYCIN; STAT3 PROTEIN; TESTOSTERONE; UNCLASSIFIED DRUG;

ACYLATION; ARCUATE NUCLEUS; BODY FAT; BODY WEIGHT; CELL LINE; DELAYED PUBERTY; DEVELOPMENTAL STAGE; ENERGY BALANCE; ENERGY EXPENDITURE; ENERGY HOMEOSTASIS; FAT MASS; FEEDBACK SYSTEM; FERTILITY; FOOD DEPRIVATION; FOOD INTAKE; FUNCTIONAL GENOMICS; GENE EXPRESSION; GENITAL SYSTEM; GLUCOSE HOMEOSTASIS; GONAD; GONAD FUNCTION; GONADOTROPIN RELEASE; GROWTH HORMONE RELEASE; HOMEOSTASIS; HORMONAL REGULATION; HUMAN; HYPERLEPTINEMIA; HYPOGONADISM; HYPOGONADOTROPIC HYPOGONADISM; HYPOPHYSIS; HYPOTHALAMUS; INFERTILITY; INSULIN RELEASE; LIFESPAN; LUTEINIZING HORMONE BLOOD LEVEL; LUTEINIZING HORMONE RELEASE; MALNUTRITION; MATURATION; MEDIOBASAL HYPOTHALAMUS; METABOLIC REGULATION; METABOLIC STRESS; NERVE CELL NETWORK; NEUROSECRETION; NONHUMAN; NUTRIENT; OVULATION; PHENOTYPE; PRIMARY CELL CULTURE; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PUBERTY; PULSE RATE; REPRODUCTION; REVIEW; SEX DIFFERENCE; SEXUAL INFANTILISM; TESTOSTERONE BLOOD LEVEL; UTERUS WEIGHT; WHITE ADIPOSE TISSUE;

ANIMALS; ENERGY METABOLISM; FEMALE; FERTILITY; GHRELIN; GONADS; HUMANS; HYPOTHALAMO-HYPOPHYSEAL SYSTEM; LEPTIN; MALE;

EID: 84890546876     PISSN: 00185043     EISSN: 14394286     Source Type: Journal    
DOI: 10.1055/s-0033-1355399     Document Type: Review

References (101)

1. Schwartz N. B. Neuroendocrine regulation of reproductive cyclicity. In: Conn P. M., Freeman M. E. (eds.) Neuroendocrinology in Physiology and Medicine. Totowa, New Jersey Humana Press: 2000; 135 146
2. Tena-Sempere M., Huhtaniemi I. Gonadotropins and gonadotropin receptors. In: Fauser BCJ M. (ed.) Reproductive Medicine - Molecular, Cellular and Genetic Fundamentals. New York Partenon Publishing: 2003; 225 244
3. Fink G. Neuroendocrine regulation of pituitary function: general principles. In: Conn P. M., Freeman M. E. (eds.) Neuroendocrinology in Physiology and Medicine. Totowa, New Jersey Humana Press: 2000; 107 134
4. Fernandez-Fernandez R., Martini A. C., Navarro V. M., Castellano J. M., Dieguez C., Aguilar E., Pinilla L., Tena-Sempere M. Novel signals for the integration of energy balance and reproduction. Mol Cell Endocrinol: 2006; 254-255 127 132
5. Navarro V. M., Castellano J. M., Garcia-Galiano D., Tena-Sempere M. Neuroendocrine factors in the initiation of puberty: The emergent role of kisspeptin. Rev Endocr Metab Disord: 2007; 8 11 20
6. Casanueva F. F., Dieguez C. Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol: 1999; 20 317 363
7. Tena-Sempere M. Ghrelin as a pleotrophic modulator of gonadal function and reproduction. Nat Clin Pract Endocrinol Metab: 2008; 4 666 674
8. Pinilla L., Aguilar E., Dieguez C., Millar R. P., Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev: 2012; 92 1235 1316
9. Castellano J. M., Bentsen A. H., Mikkelsen J. D., Tena-Sempere M. Kisspeptins: Bridging energy homeostasis and reproduction. Brain Res: 2010; 1364 129 138
10. Acosta-Martinez M. PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction. Front Endocrinol (Lausanne): 2012; 2 110
11. Elias C. F., Purohit D. Leptin signaling and circuits in puberty and fertility. Cell Mol Life Sci: 2012; 70 841 862
12. Elias C. F. Leptin action in pubertal development: recent advances and unanswered questions. Trends Endocrinol Metab: 2012; 23 9 15
13. Hill J. W., Elmquist J. K., Elias C. F. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab: 2008; 294 E827 E832
14. Xu Y., Faulkner L. D., Hill J. W. Cross-Talk between Metabolism and Reproduction: The Role of POMC and SF1 Neurons. Front Endocrinol (Lausanne): 2012; 2 98
15. Tena-Sempere M. Roles of ghrelin and leptin in the control of reproductive function. Neuroendocrinology: 2007; 86 229 241
16. Halaas J. L., Gajiwala K. S., Maffei M., Cohen SL, Chait B. T., Rabinowitz D., Lallone R. L., Burley S. K., Friedman J. M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science: 1995; 269 543 546
17. Ahima R. S., Saper C. B., Flier J. S., Elmquist J. K. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol: 2000; 21 263 307
18. Cheung C. C., Thornton J. E., Kuijper J. L., Weigle D. S., Clifton D. K., Steiner R. A. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology: 1997; 138 855 858
19. Roa J., Garcia-Galiano D., Castellano J. M., Gaytan F., Pinilla L., Tena-Sempere M. Metabolic control of puberty onset: new players, new mechanisms. Mol Cell Endocrinol: 2010; 324 87 94
20. Ahima R. S., Dushay J., Flier S. N., Prabakaran D., Flier J. S. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest: 1997; 99 391 395
21. Chehab F. F., Mounzih K., Lu R., Lim M. E. Early onset of reproductive function in normal female mice treated with leptin. Science: 1997; 275 88 90
22. Barash I. A., Cheung C. C., Weigle D. S., Ren H., Kabigting E. B., Kuijper J. L., Clifton D. K. Leptin is a metabolic signal to the reproductive system. Endocrinology: 1996; 137 3144 3147
23. Castellano J. M., Roa J., Luque R. M., Dieguez C., Aguilar E., Pinilla L., Tena-Sempere M. KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications. Peptides: 2009; 30 139 145
24. Garcia-Mayor R. V., Andrade M. A., Rios M., Lage M., Dieguez C., Casanueva F. F. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. J Clin Endocrinol Metab: 1997; 82 2849 2855
25. Plant T. M., Durrant A. R. Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta). Endocrinology: 1997; 138 4505 4508
26. Chan J. L., Heist K., DePaoli A. M., Veldhuis J. D., Mantzoros C. S. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest: 2003; 111 1409 1421
27. Caprio M., Fabbrini E., Isidori A. M., Aversa A., Fabbri A. Leptin in reproduction. Trends Endocrinol Metab: 2001; 12 65 72
28. Tena-Sempere M., Barreiro M. L. Leptin in male reproduction: the testis paradigm. Mol Cell Endocrinol: 2002; 188 9 13
29. Tena-Sempere M., Pinilla L., Gonzalez L. C., Dieguez C., Casanueva F. F., Aguilar E. Leptin inhibits testosterone secretion from adult rat testis in vitro. J Endocrinol: 1999; 161 211 218
30. True C., Kirigiti M. A., Kievit P., Grove K. L., Susan Smith M. Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance. J Neuroendocrinol: 2011; 23 1099 1112
31. Szymanski L. A., Schneider J. E., Friedman M. I., Ji H., Kurose Y., Blache D., Rao A., Dunshea F. R., Clarke I. J. Changes in insulin, glucose and ketone bodies, but not leptin or body fat content precede restoration of luteinising hormone secretion in ewes. J Neuroendocrinol: 2007; 19 449 460
32. Cummings D. E., Overduin J. Gastrointestinal regulation of food intake. J Clin Invest: 2007; 117 13 23
33. van der Lely A. J., Tschop M., Heiman M. L., Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev: 2004; 25 426 457
34. Sun Y., Asnicar M., Smith R. G. Central and peripheral roles of ghrelin on glucose homeostasis. Neuroendocrinology: 2007; 86 215 228
35. Zigman J. M., Elmquist J. K. Minireview: From anorexia to obesity - the yin and yang of body weight control. Endocrinology: 2003; 144 3749 3756
36. Tena-Sempere M. Ghrelin and reproduction: ghrelin as novel regulator of the gonadotropic axis. Vitam Horm: 2008; 77 285 300
37. Fernandez-Fernandez R., Tena-Sempere M., Navarro V. M., Barreiro M. L., Castellano J. M., Aguilar E., Pinilla L. Effects of ghrelin upon gonadotropin-releasing hormone and gonadotropin secretion in adult female rats: in vivo and in vitro studies. Neuroendocrinology: 2005; 82 245 255
38. Martini A. C., Fernandez-Fernandez R., Tovar S., Navarro V. M., Vigo E., Vazquez M. J., Davies J. S., Thompson N. M., Aguilar E., Pinilla L., Wells T., Dieguez C., Tena-Sempere M. Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats. Endocrinology: 2006; 147 2374 2382
39. Fernandez-Fernandez R., Navarro V. M., Barreiro M. L., Vigo E. M., Tovar S., Sirotkin A. V., Casanueva F. F., Aguilar E., Dieuguez C., Pinilla L., Tena-Sempere M. Effects of chronic hyperghrelinemia on puberty onset and pregnancy outcome in the rat. Endocrinology: 2005; 146 3018 3025
40. Soriano-Guillen L., Barrios V., Chowen J. A., Sánchez I., Vila S., Quero J., Argente J. Ghrelin levels from fetal life through early adulthood: relationship with endocrine and metabolic and anthropometric measures. J Pediatr: 2004; 144 30 35
41. Furuta M., Funabashi T., Kimura F. Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochem Biophys Res Commun: 2001; 288 780 785
42. Fernandez-Fernandez R., Tena-Sempere M., Aguilar E., Pinilla L. Ghrelin effects on gonadotropin secretion in male and female rats. Neurosci Lett: 2004; 362 103 107
43. Vulliemoz N. R., Xiao E., Xia-Zhang L., Germond M., Rivier J., Ferin M. Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab: 2004; 89 5718 5723
44. Iqbal J., Kurose Y., Canny B., Clarke I. J. Effects of central infusion of ghrelin on food intake and plasma levels of growth hormone, luteinizing hormone, prolactin, and cortisol secretion in sheep. Endocrinology: 2006; 147 510 519
45. Kluge M., Schussler P., Uhr M., Yassouridis A., Steiger A. Ghrelin suppresses secretion of luteinizing hormone in humans. J Clin Endocrinol Metab: 2007; 92 3202 3205
46. Lanfranco F., Bonelli L., Baldi M., Me E., Broglio F., Ghigo E. Acylated ghrelin inhibits spontaneous LH pulsatility and responsiveness to naloxone, but not that to GnRH, in young men. Evidence for a central inhibitory action of ghrelin on the gonadal axis. J Clin Endocrinol Metab: 2008; 93 3633 3639
47. Harrison J. L., Miller D. W., Findlay P. A., Adam C. L. Photoperiod influences the central effects of ghrelin on food intake, GH and LH secretion in sheep. Neuroendocrinology: 2008; 87 182 192
48. Lanfranco F., Motta G., Baldi M., Gasco V., Grottoli S., Benso A., Broglio F., Ghigo E. Ghrelin and anterior pituitary function. Front Horm Res: 2010; 38 206 211
49. Fang F., Wang L., Zhang Y., Li Y., Su S., Zhang X. Role of ghrelin on estrogen and progesterone secretion in the adult rat ovary during estrous cycle. Syst Biol Reprod Med: 2012; 58 116 119
50. Sirotkin A. V., Chrenkova M., Nitrayova S., Patras P., Darlak K., Valenzuela F., Pinilla L., Tena-Sempere M. Effects of chronic food restriction and treatments with leptin or ghrelin on different reproductive parameters of male rats. Peptides: 2008; 29 1362 1368
51. Moshtaghi-Kashanian G. R., Razavi F. Ghrelin and leptin levels in relation to puberty and reproductive function in patients with beta-thalassemia. Hormones (Athens): 2009; 8 207 213
52. Messini C. I., Dafopoulos K., Chalvatzas N., Georgoulias P., Messinis I. E. Effect of ghrelin on gonadotrophin secretion in women during the menstrual cycle. Hum Reprod: 2009; 24 976 981
53. Yang J., Brown M. S., Liang G., Grishin N. V., Goldstein J. L. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell: 2008; 132 387 396
54. Gutierrez J. A., Solenberg P. J., Perkins D. R., Willency J. A., Knieman M. D., Jin Z., Witcher D. R., Luo S., Oniya J. E., Hale J. E. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA: 2008; 105 6320 6325
55. Cunningham M. J., Clifton D. K., Steiner R. A. Leptin's actions on the reproductive axis: perspectives and mechanisms. Biol Reprod: 1999; 60 216 222
56. Pralong F. P. Insulin and NPY pathways and the control of GnRH function and puberty onset. Mol Cell Endocrinol: 2010; 324 82 86
57. Herbison A. E., Pape J. R. New evidence for estrogen receptors in gonadotropin-releasing hormone neurons. Front Neuroendocrinol: 2001; 22 292 308
58. Garcia-Galiano D., Pinilla L., Tena-Sempere M. Sex steroids and the control of the Kiss1 system: developmental roles and major regulatory actions. J Neuroendocrinol: 2012; 24 22 33
59. Magni P., Vettor R., Pagano C., Calcagno A., Bretta E., Messi E., Zanisi M., Martini L., Motta M. Expression of a leptin receptor in immortalized gonadotropin-releasing hormone-secreting neurons. Endocrinology: 1999; 140 1581 1585
60. Salvi R., Castillo E., Voirol M. J., Glauser M., Rey J-P, Gaillard R. C., Vollenwieder P., Pralong F. P. Gonadotropin-releasing hormone-expressing neurons immortalized conditionally are activated by insulin: implication of the mitogen-activated protein kinase pathway. Endocrinology: 2006; 147 816 826
61. DiVall S. A., Radovick S., Wolfe A. Egr-1 binds the GnRH promoter to mediate the increase in gene expression by insulin. Mol Cell Endocrinol: 2007; 270 64 72
62. Quennell J. H., Mulligan A. C., Tups A., Liu X., Phipps S. J., Kemp C. J., Herbison A. E., Grattan D. R., Anderson G. M. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology: 2009; 150 2805 2812
63. Finn P. D., Cunningham M. J., Pau KY F., Spies H. G., Clifton D. K., Steiner R. A. The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey. Endocrinology: 1998; 139 4652 4662
64. Hakansson M. L., Brown H., Ghilardi N., Skoda R. C., Meister B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci: 1998; 18 559 572
65. Bruning J. C., Gautam D., Burks D. J., Gillette J., Schubert M., Orban P. C., Klein R., Krone W., Müller-Wieland D., Kahn C. R. Role of brain insulin receptor in control of body weight and reproduction. Science: 2000; 289 2122 2125
66. Divall S. A., Williams T. R., Carver S. E., Koch L., Brüning J. C., Kahn C. R., Wondisford F., Radovick S., Wolfe A. Divergent roles of growth factors in the GnRH regulation of puberty in mice. J Clin Invest: 2010; 120 2900 2909
67. Roland A. V., Moenter S. M. Glucosensing by GnRH neurons: inhibition by androgens and involvement of AMP-activated protein kinase. Mol Endocrinol: 2011; 25 847 858
68. Smith J. T., Acohido B. V., Clifton D. K., Steiner R. A. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol: 2006; 18 298 303
69. Backholer K., Smith J. T., Rao A., Pereira A., Iqbal J., Ogawa S., Li Q., Clarke J. Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology: 2010; 151 2233 2243
70. Cravo R. M., Margatho L. O., Osborne-Lawrence S., Donato J. Jr, Atkin S., Bookout A. L., Rovinsky S., Frazzo R., Lee C. E., Gautron L., Zigman J. M., Elias C. F. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience: 2011; 173 37 56
71. Quennell J. H., Howell C. S., Roa J., Augustine R. A., Grattan D. R., Anderson G. M. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology: 2011; 152 1541 1550
72. Luque R. M., Kineman R. D., Tena-Sempere M. Regulation of Hypothalamic Expression of KiSS-1 and GPR54 Genes by Metabolic Factors: Analyses Using Mouse Models and a Cell Line. Endocrinology: 2007; 148 4601 4611
73. Castellano J. M., Navarro V. M., Fernandez-Fernandez R., Roa J., Vigo E., Pineda R., Dieguez C., Aguilar E., Pinilla L., Tena-Sempere M. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes: 2006; 55 2602 2610
74. Morelli A., Marini M., Mancina R., Luconi M., Vignozzi L., Fibbi B., Filippi S., Pezzatrini A., Forti G., Vannelli G., Maggi M. Sex steroids and leptin regulate the first Kiss (KiSS 1/G-protein-coupled receptor 54 system) in human gonadotropin-releasing-hormone-secreting neuroblasts. J Sex Med: 2008; 5 1097 1113
75. Qiu J., Fang Y., Bosch M. A., Ronnekleiv O. K., Kelly M. J. Guinea pig kisspeptin neurons are depolarized by leptin via activation of TRPC channels. Endocrinology: 2011; 152 1503 1514
76. Donato J. Jr, Cravo R. M., Frazao R., Gautron L., Scott M. M., Lachey J., Castro I. A., Margatho L. O., Lee S., Lee C., Richardson J. A., Friedman J., Chua S. Jr, Coppari R., Zigman J. M., Elmquist J. K., Elias C. F. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest: 2011; 121 355 368
77. Louis G. W., Greenwald-Yarnell M., Phillips R., Coolen L. M., Lehman M. N., Meyers M. G. Jr. Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology: 2011; 152 2302 2310
78. Hanchate N. K., Parkash J., Bellefontaine N., Mazur D., Colledge W. H., d'Anglemont de Tassigny X., Prevot V. Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation. J Neurosci: 2012; 32 932 945
79. Cravo R. M., Frazao R., Perello M., Osborne-Lawrence S., Williams K. W., Zigman J. M., Vianna C., Elias C. F. Leptin signaling in kiss1 neurons arises after pubertal development. PLoS One: 2013; 8 e58698
80. Castellano J. M., Navarro V. M., Fernandez-Fernandez R., Nogueiras R., Tovar S., Roa J., Vazque M. J., Vigo E., Casanueva F. F., Aguilar E., Pinilla L., Dieguez C., Tena-Sempere M. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology: 2005; 146 3917 3925
81. Thompson E. L., Patterson M., Murphy K. G., Smith K. L., Dhillo W. S., Todd J. F., Ghatei M. A., Bloom S. R. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol: 2004; 16 850 858
82. Fu L. Y., van den Pol A. N. Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. J Neurosci: 2010; 30 10205 10219
83. Stengel A., Wang L., Goebel-Stengel M., Tache Y. Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport: 2011; 22 253 257
84. Donato J. Jr, Silva R. J., Sita L. V., Lee S., Lee C., Lacchini S., Bittencourt J. C., Franci C. R., Canteras N. S., Elias C. F. The ventral premammillary nucleus links fasting-induced changes in leptin levels and coordinated luteinizing hormone secretion. J Neurosci: 2009; 29 5240 5250
85. Donato J. Jr, Lee C., Ratra D., Franci C. R., Canteras N. S., Elias C. P. Lesions of the ventral premammillary nucleus disrupt the dynamic changes in Kiss1 and GnRH expression characteristic of the proestrus-estrus transition. Neuroscience: 2013; 241 67 79
86. Tena-Sempere M. Ghrelin, the gonadal axis and the onset of puberty. Endocr Dev: 2013; 25 69 82
87. Lebrethon M. C., Aganina A., Fournier M., Gérard A., Parent A. S., Bourguignon J. P. Effects of in vivo and in vitro administration of ghrelin, leptin and neuropeptide mediators on pulsatile gonadotrophin-releasing hormone secretion from male rat hypothalamus before and after puberty. J Neuroendocrinol: 2007; 19 181 188
88. Vulliemoz N. R., Xiao E., Xia-Zhang L., Rivier J., Ferin M. Astressin B, a nonselective corticotropin-releasing hormone receptor antagonist, prevents the inhibitory effect of ghrelin on luteinizing hormone pulse frequency in the ovariectomized rhesus monkey. Endocrinology: 2008; 149 869 874
89. Forbes S., Li X. F., Kinsey-Jones J., O'Byrne K. Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat. Neurosci Lett: 2009; 460 143 147
90. Wullschleger S., Loewith R., Hall M. N. TOR signaling in growth and metabolism. Cell: 2006; 124 471 484
91. Chiang G. G., Abraham R. T. Targeting the mTOR signaling network in cancer. Trends Mol Med: 2007; 13 433 442
92. Tsang C. K., Qi H., Liu L. F., Zheng X. F. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today: 2007; 12 112 124
93. Martin D. E., Hall M. N. The expanding TOR signaling network. Curr Opin Cell Biol: 2005; 17 158 166
94. Schmelzle T., Hall M. N. TOR, a central controller of cell growth. Cell: 2000; 103 253 262
95. Cota D., Proulx K., Smith K. A., Kozma S. C., Thomas G., Woods S. C., Seeley R. J. Hypothalamic mTOR signaling regulates food intake. Science: 2006; 312 927 930
96. Woods S. C., Seeley R. J., Cota D. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr: 2008; 28 295 311
97. Villanueva E. C., Munzberg H., Cota D., Leshan R. L., Kopp K., Ishida-Takahashi R., Jones J. C., Fingar D. C., Seeley R. J., Myers M. G. Jr. Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology: 2009; 150 4541 4551
98. Martins L., Fernandez-Mallo D., Novelle M. G., Vázquez M. J., Tena-Sempere M., Nogueiras R., Lopez M. Hypothalamic mTOR Signaling Mediates the Orexigenic Action of Ghrelin. PLoS One: 2012; 7 e46923
99. Roa J., Garcia-Galiano D., Varela L., Sanchez-Garrido M. A., Pineda R., Castellano J. M., Ruiz-Pino F., Romero M., Aguilar E., López M., Gytan F., Diéguez C., Pinilla L., Tena-Sempere M. The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology: 2009; 150 5016 5026
100. Altarejos J. Y., Goebel N., Conkright M. D., Inoue H., Xie J., Arias C. M., Sawchenko P. E., Montminy M. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nat Med: 2008; 14 1112 1117
101. Breuillaud L., Halfon O., Magistretti P. J., Pralong F. P., Cardinaux J. R. Mouse fertility is not dependent on the CREB coactivator Crtc1. Nat Med: 2009; 15 989 990 author reply 991