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DOI: 10.1055/s-0033-1355399
Interaction Between Energy Homeostasis and Reproduction: Central Effects of Leptin and Ghrelin on the Reproductive Axis
Publication History
received 30 May 2013
accepted 27 August 2013
Publication Date:
23 October 2013 (online)
![](https://www.thieme-connect.de/media/hmr/201313/lookinside/thumbnails/10.1055-s-0033-1355399-1.jpg)
Abstract
Reproductive maturation and function are sensitive to the metabolic state of the organism and the magnitude of body fuel reserves; hence, conditions ranging from energy insufficiency to morbid obesity impact the timing of puberty and are frequently linked to fertility problems. This phenomenon is the result of the close interplay between a diversity of nutritional cues and metabolic signals (including hormones) with different elements of the so-called hypothalamic-pituitary-gonadal (HPG) axis. In this review, we will focus our attention on the ‘reproductive’ roles of 2 key metabolic hormones, namely, the adipose signal, leptin, and the gut hormone, ghrelin. These 2 factors, which have been proposed to operate as functional antagonists in the control of metabolism and energy homeostasis, are also provided with important, and in many cases opposite, roles in the regulation of puberty onset and gonadal function. We will provide herein an update view of the reproductive effects of leptin and ghrelin, with a major emphasis on the actions of these 2 key hormones upon the central elements of the HPG axis, including their putative effects on Kiss1 and other reproductive neuronal networks. This will help to understand the mechanisms whereby reproductive function is gated and dynamically regulated by metabolic signals at different key developmental stages, such as puberty and adulthood.
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References
- 1 Schwartz NB. Neuroendocrine regulation of reproductive cyclicity. In: Conn PM, Freeman ME. (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 BCJM. (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 PM, Freeman ME. (eds.) Neuroendocrinology in Physiology and Medicine. Totowa, New Jersey: Humana Press; 2000: 107-134
- 4 Fernandez-Fernandez R, Martini AC, Navarro VM, Castellano JM, 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 VM, Castellano JM, 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 FF, 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 RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 2012; 92: 1235-1316
- 9 Castellano JM, Bentsen AH, Mikkelsen JD, 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 CF, Purohit D. Leptin signaling and circuits in puberty and fertility. Cell Mol Life Sci 2012; 70: 841-862
- 12 Elias CF. Leptin action in pubertal development: recent advances and unanswered questions. Trends Endocrinol Metab 2012; 23: 9-15
- 13 Hill JW, Elmquist JK, Elias CF. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab 2008; 294: E827-E832
- 14 Xu Y, Faulkner LD, Hill JW. 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 JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-546
- 17 Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 2000; 21: 263-307
- 18 Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. 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 JM, 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 RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 1997; 99: 391-395
- 21 Chehab FF, Mounzih K, Lu R, Lim ME. Early onset of reproductive function in normal female mice treated with leptin. Science 1997; 275: 88-90
- 22 Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, Clifton DK. Leptin is a metabolic signal to the reproductive system. Endocrinology 1996; 137: 3144-3147
- 23 Castellano JM, Roa J, Luque RM, 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 RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF. 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 TM, Durrant AR. 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 JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. 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 AM, Aversa A, Fabbri A. Leptin in reproduction. Trends Endocrinol Metab 2001; 12: 65-72
- 28 Tena-Sempere M, Barreiro ML. Leptin in male reproduction: the testis paradigm. Mol Cell Endocrinol 2002; 188: 9-13
- 29 Tena-Sempere M, Pinilla L, Gonzalez LC, Dieguez C, Casanueva FF, Aguilar E. Leptin inhibits testosterone secretion from adult rat testis in vitro. J Endocrinol 1999; 161: 211-218
- 30 True C, Kirigiti MA, Kievit P, Grove KL, 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 LA, Schneider JE, Friedman MI, Ji H, Kurose Y, Blache D, Rao A, Dunshea FR, Clarke IJ. 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 DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest 2007; 117: 13-23
- 33 van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004; 25: 426-457
- 34 Sun Y, Asnicar M, Smith RG. Central and peripheral roles of ghrelin on glucose homeostasis. Neuroendocrinology 2007; 86: 215-228
- 35 Zigman JM, Elmquist JK. 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 VM, Barreiro ML, Castellano JM, 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 AC, Fernandez-Fernandez R, Tovar S, Navarro VM, Vigo E, Vazquez MJ, Davies JS, Thompson NM, 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 VM, Barreiro ML, Vigo EM, Tovar S, Sirotkin AV, Casanueva FF, 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 JA, 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 NR, 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 IJ. 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 JL, Miller DW, Findlay PA, Adam CL. 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 AV, 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 GR, 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 CI, Dafopoulos K, Chalvatzas N, Georgoulias P, Messinis IE. Effect of ghrelin on gonadotrophin secretion in women during the menstrual cycle. Hum Reprod 2009; 24: 976-981
- 53 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: 387-396
- 54 Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knieman MD, Jin Z, Witcher DR, Luo S, Oniya JE, Hale JE. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA 2008; 105: 6320-6325
- 55 Cunningham MJ, Clifton DK, Steiner RA. Leptin’s actions on the reproductive axis: perspectives and mechanisms. Biol Reprod 1999; 60: 216-222
- 56 Pralong FP. Insulin and NPY pathways and the control of GnRH function and puberty onset. Mol Cell Endocrinol 2010; 324: 82-86
- 57 Herbison AE, Pape JR. 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 MJ, Glauser M, Rey J-P, Gaillard RC, Vollenwieder P, Pralong FP. 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 SA, 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 JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, Herbison AE, Grattan DR, Anderson GM. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 2009; 150: 2805-2812
- 63 Finn PD, Cunningham MJ, Pau KYF, Spies HG, Clifton DK, Steiner RA. The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey. Endocrinology 1998; 139: 4652-4662
- 64 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: 559-572
- 65 Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 2000; 289: 2122-2125
- 66 Divall SA, Williams TR, Carver SE, Koch L, Brüning JC, Kahn CR, 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 AV, Moenter SM. Glucosensing by GnRH neurons: inhibition by androgens and involvement of AMP-activated protein kinase. Mol Endocrinol 2011; 25: 847-858
- 68 Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol 2006; 18: 298-303
- 69 Backholer K, Smith JT, 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 RM, Margatho LO, Osborne-Lawrence S, Donato Jr J, Atkin S, Bookout AL, Rovinsky S, Frazzo R, Lee CE, Gautron L, Zigman JM, Elias CF. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 2011; 173: 37-56
- 71 Quennell JH, Howell CS, Roa J, Augustine RA, Grattan DR, Anderson GM. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology 2011; 152: 1541-1550
- 72 Luque RM, Kineman RD, 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 JM, Navarro VM, 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 MA, Ronnekleiv OK, Kelly MJ. Guinea pig kisspeptin neurons are depolarized by leptin via activation of TRPC channels. Endocrinology 2011; 152: 1503-1514
- 76 Donato Jr J, Cravo RM, Frazao R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua Jr S, Coppari R, Zigman JM, Elmquist JK, Elias CF. 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 GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Meyers Jr MG. Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 2011; 152: 2302-2310
- 78 Hanchate NK, Parkash J, Bellefontaine N, Mazur D, Colledge WH, 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 RM, Frazao R, Perello M, Osborne-Lawrence S, Williams KW, Zigman JM, Vianna C, Elias CF. Leptin signaling in kiss1 neurons arises after pubertal development. PLoS One 2013; 8: e58698
- 80 Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, Vazque MJ, Vigo E, Casanueva FF, 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 EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol 2004; 16: 850-858
- 82 Fu LY, van den Pol AN. 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 Jr J, Silva RJ, Sita LV, Lee S, Lee C, Lacchini S, Bittencourt JC, Franci CR, Canteras NS, Elias CF. The ventral premammillary nucleus links fasting-induced changes in leptin levels and coordinated luteinizing hormone secretion. J Neurosci 2009; 29: 5240-5250
- 85 Donato Jr J, Lee C, Ratra D, Franci CR, Canteras NS, Elias CP. 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 MC, Aganina A, Fournier M, Gérard A, Parent AS, Bourguignon JP. 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 NR, 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 XF, 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 MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471-484
- 91 Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med 2007; 13: 433-442
- 92 Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007; 12: 112-124
- 93 Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol 2005; 17: 158-166
- 94 Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253-262
- 95 Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science 2006; 312: 927-930
- 96 Woods SC, Seeley RJ, Cota D. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr 2008; 28: 295-311
- 97 Villanueva EC, Munzberg H, Cota D, Leshan RL, Kopp K, Ishida-Takahashi R, Jones JC, Fingar DC, Seeley RJ, Myers Jr MG. 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 MG, Vázquez MJ, 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 MA, Pineda R, Castellano JM, 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 JY, Goebel N, Conkright MD, Inoue H, Xie J, Arias CM, Sawchenko PE, 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 PJ, Pralong FP, Cardinaux JR. Mouse fertility is not dependent on the CREB coactivator Crtc1. Nat Med 2009; 15: 989-990 author reply 991