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Energy balance and puberty onset: emerging role of central mTOR signaling
Abstract
The onset of puberty is gated by body energy reserves and nutritional cues. The adipose hormone leptin is an essential signal for the metabolic control of puberty, through mechanisms that are yet to be fully characterized. Mammalian target of rapamycin (mTOR), an energetic cell sensor, operates at specific hypothalamic nuclei as a transducer for leptin effects on feeding and energy homeostasis. This review summarizes recent experimental evidence supporting a role for central mTOR signaling in puberty onset. These findings are discussed in the context of topical developments in the field, such as recognition of the roles of the cAMP responsive element-binding protein regulated transcription coactivator-1 (Crtc1) and kisspeptins in the metabolic control of reproduction, thus highlighting novel mechanisms responsible for coupling puberty and energy homeostasis.
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“In mammals, GnRH release is also regulated by the orexigenic neuropeptide Y (NPY) and kisspeptin, which relays both sex steroid and leptin signaling to GnRH neurons (49).”
From Corazonin signaling integrates energy homeostasis and lunar phase to regulate aspects of growth and sexual maturation in Platynereis (2020) · cites this paper as [49]
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“stress on Kiss1 expression and gonadotropin responsiveness to Kp had been previously explored in pubertal and adult animals (45, 46), the impact of early (postnatal) metabolic challenges on the subsequent expression and function of the hypothalamic Kiss1 system later during puberty remains largely unexplored to date.”
BackgroundInfluentialLeptin signaling and circuits in puberty and fertility
Elias, C. F., & Purohit, D. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1095-1 · Cited by 200
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Codner, E., Merino, P. M., & Tena-Sempere, M. (2012) · Human Reproduction Update · doi:10.1093/humupd/dms024 · Cited by 182
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InfluentialLeptin action in pubertal development: recent advances and unanswered questions
Elias, C. F. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.09.002 · Cited by 145
“In recent years, a series of important findings have suggested a role for cAMP responsive element-binding protein regulated transcription coactivator-1 (Crtc1) and mTOR as potential signaling pathways linking energy balance and reproduction (17, 84, 85).”
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“…suggests that, in addition to its central actions on energy homeostasis, brain mTOR signaling is also involved in the metabolic regulation of the HPG axis, and specifically in conveying, at least part of, the modulatory effects of leptin onto the reproductive brain (Roa and Tena-Sempere, 2010).”
Hypothalamic mTOR Signaling Mediates the Orexigenic Action of Ghrelin
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“Contrary to AMPK, mTOR is activated in situations of energy excess to promote anabolic pathways, the inter-relationship between AMPK and mTOR being fundamental in the control of numerous cellular activities (Roa & Tena-Sempere 2010, Lopez et al.”
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“The mTOR pathway also controls the HPG axis and the onset of puberty (379, 381).”
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Roa, J., Barroso, A., Ruíz-Pino, F., Vazquez, M. J., Seoane‐Collazo, P., Martínez‐Sánchez, N., García-Galiano, D., İlhan, T., Pineda, R., León, S., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802053115 · Cited by 82
“We have previously documented that hypothalamic signaling via the mammalian target of rapamycin (mTOR) interplays with Kiss1 in the metabolic control of puberty (28, 45).”
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Tena‐Sempere, M. (2012) · European Journal of Endocrinology · doi:10.1530/eje-12-0669 · Cited by 76
Age-dependent effects in fathead minnows from the anti-diabetic drug metformin
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“In mammals, GnRH release is also regulated by the orexigenic neuropeptide Y (NPY) and kisspeptin, which relays both sex steroid and leptin signaling to GnRH neurons (49).”
BackgroundManagement of side effects of mTOR inhibitors in tuberous sclerosis patients
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“leptin signaling) and reproductive function has also emerged (67, 68).”
BackgroundThe Genetic Basis of Delayed Puberty
Howard, S. R. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00423 · Cited by 59
“These afferents are likely to include LEPRexpressing GABA neurons from the arcuate nucleus, nitric oxide (which is required for its action) pathways, mTOR signaling, as well as kisspeptin/neuropeptide Y neurons (30, 31).”
BackgroundGerosuppressant Metformin: less is more
Menéndez, J. A., Cufí, S., Oliveras‐Ferraros, C., Vellón, L., Joven, J., & Vázquez‐Martín, A. (2011) · Aging · doi:10.18632/aging.100316 · Cited by 57
“Moreover, the well-recognized ability of CR-induced deactivation of the mTOR pathway to slow growth, fitness and the onset of reproduction [10-12] while reducing risk of cancer (i.”
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“…inflammation affects both NPY and POMC and promotes obesity. mTOR Signaling Mammalian target of rapamycin (mTOR) is a serine-theonine kinase as a sensor of energy balance, nutrients and oxygen (Roa and Tena-Sempere, 2010). mTOR is expressed in AgRP/NPY neurons in the ARC (Cota et al., 2006).”
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“In addition to a large number of studies investigating a role for mTOR in the regulation of energy homeostasis (23,28,31,32), which provide indirect evidence for a role of S6K1 in the regulation of energy homeostasis, recent studies have also provided evidence for a role of S6K1 FIG.”
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“Detailed description of the physiological roles of mTOR in the control of cellular energy homeostasis and food intake can be found elsewhere (Roa & Tena-Sempere, 2010).”
BackgroundRat BAT xenotransplantation recovers the fertility and metabolic health of PCOS mice
Du, L., Wang, Y., Li, C., Chen, L.-J., Cai, J.-Y., Xia, Z., Zeng, W., Wang, Z., Chen, X., Hu, F., et al. (2020) · Journal of Endocrinology · doi:10.1530/joe-20-0068 · Cited by 46
“Fourth, mTOR activity is important for maintaining normal metabolism, and abnormal mTOR activity levels in PCOS mice are related to abnormal energy production (Roa & Tena-Sempere 2010, Hung et al.”
BackgroundLeptin regulates neuropeptides associated with food intake and GnRH secretion
Guzmán, A., Hernández‐Coronado, C. G., Rosales‐Torres, A. M., & Hernandez-Medrano, J. H. (2018) · Annales d Endocrinologie · doi:10.1016/j.ando.2018.07.012 · Cited by 50
Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target?
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Knockdown of leptin A expression dramatically alters zebrafish development
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“That body of work revealed that leptin is a pleiotropic hormone, with well described effects on lipid metabolism, thermoregulation, immune function, reproductive maturation, angiogenesis, and bone remodeling (see [6, 14, 15,25, 47, 49] for reviews).”
BackgroundReview of the role of leptin in the regulation of male reproductive function
Zhang, J., & Gong, M. (2018) · Andrologia · doi:10.1111/and.12965 · Cited by 44
Ghrelin, the Gonadal Axis and the Onset of Puberty
Tena‐Sempere, M. (2013) · Endocrine development · doi:10.1159/000346055 · Cited by 42
Role of the adipocyte-derived hormone leptin in reproductive control
García-Galiano, D., Allen, S. J., & Elias, C. F. (2014) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2014-0017 · Cited by 40
“mTOR is a serine/threonine kinase downstream of the PI3K-Akt pathway with a key role in multiple functions, including the neuroendocrine control of the reproductive axis [89].”
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“mTOR appears to act upstream of kisspeptin and GnRH in vertebrates [47,48,49,50].”
BackgroundRola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa
Javed, Z., Qamar, U., & Sathyapalan, T. (2015) · Endokrynologia Polska · doi:10.5603/ep.2015.0066 · Cited by 30
“These findings attracted substantial attention and have been the subject of rigorous analysis in various mammalian and non-mammalian species [92, 129] and the current available neuroanatomical and functional evidence, although mainly in rodents, strongly supports the role of kisspeptins in triggering the onset of pube…”
BackgroundRNA-seq analysis of lncRNA-controlled developmental gene expression during puberty in goat & rat
Gao, X., Ye, J., Chen, Y., Luo, L., Liu, Y., Ding, J., Zhang, Y., Ling, Y., Huang, W., Zhang, X., et al. (2018) · BMC Genetics · doi:10.1186/s12863-018-0608-9 · Cited by 29
“As showed previously, the AMPK signaling pathway was a novel regulator of GnRH release, which played an important role in regulating puberty and reproduction [54, 55].”
BackgroundmTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol
González‐García, I., de Morentin, P. B. M., Estévez‐Salguero, Á., Contreras, C., Romero, A., Fernø, J., Nogueiras, R., Diéguez, C., Tena‐Sempere, M., Tovar, S. A., et al. (2018) · Journal of Endocrinology · doi:10.1530/joe-18-0190 · Cited by 26
“Specifically, hypothalamic mTOR controls puberty onset and gonadotropin secretion by regulation of Kiss1 (Roa et al. 2009, Roa & Tena-Sempere 2010).”
Calorie Restriction Modulates Reproductive Development and Energy Balance in Pre-Pubertal Male Rats
Rizzoto, G., Sekhar, D., Thundathil, J. C., Chelikani, P. K., & Kastelic, J. P. (2019) · Nutrients · doi:10.3390/nu11091993 · Cited by 26
“It is well documented that metabolic hormones including leptin, IGF-1 and insulin communicate level of body tissue reserves to the hypothalamic-pituitary-gonadal (HPG) axis [11,16,40], emphasizing importance of studying impacts of nutrition and refeeding on above-described hormones.”
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“Although the precise molecular mechanisms by which the information conveyed by this plethora of metabolic hormones is transmitted to the brain centers governing the reproductive axis are not completely elucidated, experimental studies conducted by our group in recent years have focused on addressing the potential role…”
BackgroundAnimal Modeling of Early Programming and Disruption of Pubertal Maturation
Castellano, J. M., & Tena‐Sempere, M. (2015) · Endocrine development · doi:10.1159/000438877 · Cited by 28
Bourguignon, J.-P., Juul, A., Franssen, D., Fudvoye, J., Pinson, A., & Parent, A. (2016) · Hormone Research in Paediatrics · doi:10.1159/000442748 · Cited by 27
Arginine, histidine and tryptophan: A new hope for cancer immunotherapy
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Fogarasi, A., Waele, L. D., Bartalini, G., Jóźwiak, S., Laforgia, N., Verhelst, H., Petrak, B., Pédespan, J., Witt, O., Castellana, R., et al. (2016) · BMC Neurology · doi:10.1186/s12883-016-0658-4 · Cited by 24
“While some data indicate that mTOR inhibition may partly be associated with the control of puberty onset [32], it has also been suggested that amenorrhea could be caused by TSC per se and may not be related to the treatment with mTOR inhibitors [33].”
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Michalovic, L., Currin, L., Gutierrez, K., Bellefleur, A., Glanzner, W. G., Schuermann, Y., de Macedo, M. P., Bohrer, R. C., Dicks, N., Lopez, R., et al. (2018) · Molecular Reproduction and Development · doi:10.1002/mrd.23066 · Cited by 22
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“These observations support a central role for mTOR signaling in pubertal onset and necessitate further investigations of potential effects of everolimus on growth, development and sexual maturation in children [9,19].”
BackgroundMethylation of Hypothalamic Tsc1‐mTOR Signaling in Regulation of Obesity and Obesity Resistance
Wang, Y., Diao, S., Hu, M., & Zhang, L. (2020) · BioMed Research International · doi:10.1155/2020/8723869 · Cited by 20
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“mTOR signaling pathway is found to couple the nutritional status to regulate puberty onset in rats [39].”
BackgroundOhga, H., Hirata, D., Matsumori, K., Kitano, H., Nagano, N., Yamaguchi, A., & Matsuyama, M. (2016) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2016.09.009 · Cited by 16
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“In addition, prominent among the KEGG pathways, mammalian target of rapamycin (mTOR) signaling pathway has been found to couple the nutritional status to regulate puberty onset in rats [59] and the timing of molt inManduca sexta [60].”
BackgroundProteomic analysis of hypothalamus in prepubertal and pubertal female goat
Ye, J., Yan, X., Qin, P., Gong, X., Li, H., Liu, Y., Yu, T., Zhang, Y., Ling, Y., Cao, H., et al. (2021) · Journal of Proteomics · doi:10.1016/j.jprot.2021.104411 · Cited by 13
Kisspeptins in human reproduction—future therapeutic potential
Kaur, K. K., Allahbadia, G. N., & Singh, M. (2012) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-012-9856-1 · Cited by 13
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The hippo pathway: a molecular bridge between environmental cues and pace of life
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“This network is also thought to involve AMPK (AMP-activated protein kinase), another pivotal nutrition sensor known to interact with mTOR [63].”
Backgroundde Abreu, M. S., Demin, K. A., Kotova, M. M., Mirzaei, F., Shariff, S., Kantawala, B., Zakharchenko, K. V., Kolesnikova, T. O., Dilbaryan, K., Grigoryan, A., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021530 · Cited by 10
“Finally, the initiation of puberty and the gonadotropic axis are both regulated by centrally expressed mTOR [30].”
BackgroundVazquez, M. J., Novelle, M. G., Rodríguez‐Pacheco, F., Lage, R., Varela, L., López, M., Pinilla, L., Tena‐Sempere, M., & Diéguez, C. (2020) · Cells · doi:10.3390/cells9091940 · Cited by 10
“In addition, ghrelin has been shown to activate hypothalamic mTOR signaling, while inactivation of central mTOR by rapamycin attenuated ghrelin’s orexigenic effect [15], and caused inhibition of the gonadotropic axis and puberty; this period is one of the major determinants of GH secretory status [19,20].”
BackgroundStimulation of GHRH Neuron Axon Growth by Leptin and Impact of Nutrition during Suckling in Mice
Decourtye, L., Clemessy, M., Leneuve, P., Mire, E., Ledent, T., Bouc, Y. L., & Kappeler, L. (2023) · Nutrients · doi:10.3390/nu15051077 · Cited by 8
“Leptin has been reported to act on different neuronal populations, including the NPY neurons of the arcuate nucleus to control metabolism, and the ventral premammillary nucleus neurons to generate a permissive signal for reproduction [14,23,24].”
BackgroundMechanisms linking energy balance and reproduction: impact of prenatal environment
Keen‐Rhinehart, E. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0004 · Cited by 7
“It is likely that the central inhibition of mTOR nullifies the action of leptin on the HPG axis via changes in kisspeptin because pharmacological blockade of mTOR also significantly decreases kisspeptin expression in the Arc and AVPV in rats [89].”
BackgroundCastro-González, D., Fuente-Martín, E., Sanchez-Garrido, M. A., Argente-Arizón, P., Tena‐Sempere, M., Barrios, V., Chowen, J. A., & Argente, J. (2015) · Endocrinology · doi:10.1210/en.2014-1759 · Cited by 7
p53 Mediates GnRH Secretion via Lin28/let-7 System in GT1-7 Cells
Chen, T., Wu, H., Chen, X., Xie, R., Wang, F., Sun, H., & Chen, L. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s279901 · Cited by 7
Analysis of protein phosphorylation sites in the hypothalamus tissues of pubescent goats
Yan, X., Gong, X., Lin, T., Lin, M., Qin, P., Ye, J., Li, H., Hong, Q., Li, M., Liu, Y., et al. (2022) · Journal of Proteomics · doi:10.1016/j.jprot.2022.104574 · Cited by 7
Li, Q., Chao, T., Wang, Y., Xuan, R., Guo, Y., He, P., Zhang, L., & Wang, J. (2024) · BMC Genomics · doi:10.1186/s12864-024-10735-y · Cited by 6
“ANXA7 is also involved in glucose metabolism by regulating insulin secretion [49, 51], and energy reserve levels and metabolic status plays important roles in the sexual maturation of female animals [52].”
BackgroundInterplay of KNDy and nNOS neurons: A new possible mechanism of GnRH secretion in the adult brain
Prashar, V., Arora, T., Singh, R., Sharma, A., & Parkash, J. (2021) · Reproductive Biology · doi:10.1016/j.repbio.2021.100558 · Cited by 7
Thind, A. S., Vitali, V., Guarracino, M. R., & Catania, F. (2020) · Genome Biology and Evolution · doi:10.1093/gbe/evaa052 · Cited by 6
Muricholic acid mediates puberty initiation via the hypothalamic TGR5 signaling pathway
Wang, S., Huang, K., Liu, A., Wang, S., Jiang, R., Chen, W., Wang, H., Ullah, R., Xue, C., Wu, W., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2511404122 · Cited by 5
“Recent evidence has indicated that the mTOR signaling pathway, specifically mTORC1, within hypothalamic neuronal populations, plays a crucial role in controlling puberty onset ( 52 ).”
Zhao, J., Li, S., Gong, Q.-Q., Ding, L.-C., Jin, Y., Zhang, J., Gao, J., & Sun, X. (2016) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b1600276 · Cited by 5
Li, Q., Chao, T., Wang, Y., Xuan, R., Guo, Y., He, P., Zhang, L., & Wang, J. (2024) · Frontiers in Veterinary Science · doi:10.3389/fvets.2024.1404681 · Cited by 4
“In mammals, LEP acts on neural circuits in the hypothalamus to regulate feeding and energy metabolism (44), and in addition, leptin can be involved in the regulation of puberty through mTOR (9). qRT-PCR verification of lncRNA expression levels in hypothalamus at four developmental stages of Jining…”
BackgroundAkkaya, H. (2021) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093021020095 · Cited by 3
Han, R., Han, L., Xia, Y., Guo, M., & Li, H. (2021) · Animal Biotechnology · doi:10.1080/10495398.2021.1924762 · Cited by 3
“The PI3K/AKT signaling pathway can promote a large number of blood vessels to meet nutrient supply by activating the downstream of the mTOR signaling pathway.(42,43) The lncRNAs that interact with these genes may play a unique role in the MP of the antler growth (TCONS_00087144, TCONS_00072627, and TCONS_00007422).”
BackgroundDudás, B., & Merchenthaler, I. J. (2021) · Brain Structure and Function · doi:10.1007/s00429-021-02416-3 · Cited by 3
O neuropeptídeo kisspeptina e a reprodução animal: uma revisão
Dias, J. C. O., Veloso, C. M., Donzele, R. F. M. D. O., & de Carvalho, G. R. (2018) · Multi-Science Journal · doi:10.33837/msj.v1i2.76 · Cited by 2
Jin, C., & Zhao, G. (2024) · Metabolites · doi:10.3390/metabo14030137 · Cited by 4
“…onset and partially reversing the undernutrition-induced reduction in gonadotropin levels and puberty [35,59], while inhibiting mTOR activity delays puberty onset by reducing Kiss1 gene expression in the arcuate nucleus and lowering the circulating levels of LH and estradiol in female rats [35,59].”
BackgroundPathogenesis of ovarian dysfunction in women with diabetes mellitus 1 type
Tolpygina, M. G., Ивановна, А. Е., Borovik, N. V., & Tiselko, A. V. (2018) · Journal of obstetrics and women s diseases · doi:10.17816/jowd6715-12 · Cited by 1
MiR-505-3p, a New Repressor of Puberty Onset in Female MicePreprint
Li, T., Wang, M., Zhou, Y., Li, Y., Chen, L., Xu, F., Li, K., & Xiao, J. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/271718 · Cited by 1
Neuroendocrine Disruption of Reproduction
Fudvoye, J., Bourguignon, J.-P., & Parent, A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.65356-4 · Cited by 1
Control hormonal de la homeostásis energética: de la célula al cerebro
Osorio-Paz, I., & Sacanelles, R. S. (2012) · REB. Revista de educación bioquímica
González, D. (2014) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Gonadotropin-Dependent Precocious Puberty; Female and Male
Mul, D., Oostdijk, W., & Drop, S. L. S. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.03912-x
Ghrelin, Lipid Metabolism, and Metabolic Syndrome
de Morentin, P. B. M., Tovar, S. A., Nogueiras, R., López, M., & Diéguez, C. (2013) · Wiley eBooks · doi:10.1002/9781118395318.ch29
Neuroendocrine and Molecular Mechanisms for the Metabolic Control of Puberty: Recent Developments
Tena‐Sempere, M. (2014) · Research and perspectives in endocrine interactions · doi:10.1007/978-3-319-09168-6_9
ESTUDO DE VIA DE PI3K EM MELANOMAS DE CORÓIDE
Freeman, G. M. (2012)
Neuroendocrine Disruption of Reproduction
Fudvoye, J., Bourguignon, J.-P., & Parent, A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11074-8
Metabolic regulation of female puberty via hypothalamic AMPK-kisspeptin signaling
Roa, J., Barroso, A., Ruíz-Pino, F., Vazquez, M. J., Seoane‐Collazo, P., Martínez‐Sánchez, N., García-Galiano, D., İlhan, T., Pineda, R., León, S., et al. (2019) · Yearbook of pediatric endocrinology · doi:10.1530/ey.16.7.3
Metadata
- Authors
- Roa, J., & Tena-Sempere, M.
- Affiliations
- University of Córdoba (ES)
- ORCID
- Roa, Juan
- Venue
- Trends in Endocrinology & Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 21
- Issue
- 9
- Pages
- 519-528
- ISSN
- 1043-2760 (ISSN-L)
- OpenAlex
- W2134113504
- Cited by
- 106
- References
- 74
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 14 · 2017: 4 · 2016: 9 · 2015: 9 · 2014: 4 · 2013: 5 · 2012: 13
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Keywords
- puberty onset, mTOR signaling, leptin, hypothalamus, energy homeostasis, CRTC1, kisspeptin, energy balance, reproductive development
- MeSH terms
- Animals, Energy Metabolism, Humans, Puberty, Signal Transduction, Leptin, TOR Serine-Threonine Kinases
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