Connecting metabolism and gonadal function: Novel central neuropeptide pathways involved in the metabolic control of puberty and fertility
Abstract
Albeit essential for perpetuation of species, reproduction is an energy-demanding function that can be adjusted to body metabolic status. Reproductive maturation and function can be suppressed in conditions of energy deficit, but can be altered also in situations of persistent energy excess, e.g., morbid obesity. This metabolic-reproductive integration, of considerable pathophysiological relevance to explain different forms of perturbed puberty and sub/infertility, is implemented by the concerted action of numerous central and peripheral regulators, which impinge at different levels of the hypothalamic-pituitary-gonadal (HPG) axis, permitting a tight fit between nutritional/energy status and gonadal function. We summarize here the major physiological mechanisms whereby nutritional and metabolic cues modulate the maturation and function of the HPG axis. We will focus on recent progress on the major central neuropeptide pathways, including kisspeptins, neurokinin B and the products of POMC and NPY neurons, which convey metabolic information to GnRH neurons, as major hierarchical hub of our reproductive brain.
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ARNKISS neurons integrate multiple internal homeostatic and external environmental cues to establish an appropriate pattern of pulsatile LH secretion for reproductive function.
“Several lines of evidence indicate that ARNKISS neurons integrate multiple internal homeostatic and external environmental cues to establish an appropriate pattern of pulsatile LH secretion for reproductive function1,12–15.”
From Brainstem noradrenergic modulation of the kisspeptin neuron GnRH pulse generator in mice (2025) · cites this paper as [14]
Cites
The <i>GPR54</i> Gene as a Regulator of Puberty
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035322 · Cited by 2,557 · see citing works
Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834399100 · Cited by 2,431 · cited 1× · see citing works
“…gene encoding kisspeptins or their receptor cause absence of puberty onset and hypogonadotropic hypogonadism in humans (Seminara et al., 2003; de Roux et al., 2003), and kisspeptins are extremely potent secretagogues of gonadotropins in different mammalian species, including humans (Pinilla et…”
BackgroundCoexpression of Agrp and NPY in fasting-activated hypothalamic neurons
Hahn, T. M., Breininger, J. F., Baskin, D. G., & Schwartz, M. W. (1998) · Nature Neuroscience · doi:10.1038/1082 · Cited by 1,164 · see citing works
Topaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Serin, A., Mungan, N. O., Cook, J. R., Ozbek, M. N., et al. (2009) · Nature Genetics · doi:10.1038/ng.306 · Cited by 961 · see citing works
Lehman, M. N., Coolen, L. M., & Goodman, R. L. (2010) · Endocrinology · doi:10.1210/en.2010-0022 · Cited by 768 · see citing works
Insulin Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production
Könner, A. C., Janoschek, R., Plum, L., Jordan, S. D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G. S., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.004 · Cited by 695 · see citing works
Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice
Thornton, J. E., Cheung, C. C., Clifton, D. K., & Steiner, R. A. (1997) · Endocrinology · doi:10.1210/endo.138.11.5651 · Cited by 437 · cited 2× · see citing works
“, 1999), while obese, leptin-deficient ob/ob mice show reduced POMC mRNA expression in the ARC, which can be rescued by leptin administration (Thornton et al., 1997).”
BackgroundCharacterization of Kiss1 neurons using transgenic mouse models
Cravo, R. M., Margatho, L. O., Osborne-Lawrence, S., Donato, J., Atkin, S., Bookout, A. L., Rovinsky, S., Frazão, R., Lee, C. E., Gautron, L., et al. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2010.11.022 · Cited by 353 · see citing works
van de Wall, E., Leshan, R., Xu, A. W., Balthasar, N., Coppari, R., Liu, S. M., Jo, Y. H., MacKenzie, R. G., Allison, D. B., Dun, N. J., et al. (2008) · Endocrinology · doi:10.1210/en.2007-1132 · Cited by 338 · see citing works
Burcelin, R., Thorens, B., Glauser, M., Gaillard, R. C., & Pralong, F. P. (2003) · Endocrinology · doi:10.1210/en.2003-0457 · Cited by 173 · see citing works
Epigenetic regulation of female puberty
Lomniczi, A., Wright, H., & Ojeda, S. R. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.08.003 · Cited by 136 · see citing works
Hrabovszky, E., Sipos, M. T., Molnár, C. S., Ciofi, P., Borsay, B. Á., Gergely, P., Herczeg, L., Bloom, S. R., Ghatei, M. A., Dhillo, W. S., et al. (2012) · Endocrinology · doi:10.1210/en.2012-1545 · Cited by 124 · see citing works
Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction
Israel, D. D., Sheffer-Babila, S., de Luca, C., Jo, Y.-H., Liu, S. M., Xia, Q., Spergel, D. J., Dun, S. L., Dun, N. J., & Chua, S. C. (2012) · Endocrinology · doi:10.1210/en.2011-1822 · Cited by 109 · see citing works
Hypothalamic proopiomelanocortin (POMC) neurons have a cholinergic phenotype
Meister, B., Gömüç, B., Suarez, E., Ishii, Y., Dürr, K., & Gillberg, L. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05157.x · Cited by 75 · see citing works
Moret, M., Stettler, R., Rodieux, F., Gaillard, R. C., Waeber, G., Wirthner, D., Giusti, V., Tappy, L., & Pralong, F. P. (2009) · Neuroendocrinology · doi:10.1159/000160911 · Cited by 72 · see citing works
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Metabolic regulation of kisspeptin — the link between energy balance and reproduction
Navarro, V. M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0363-7 · Cited by 240 · see citing works
Hypogonadism and male obesity: Focus on unresolved questions
Grossmann, M. (2018) · Clinical Endocrinology · doi:10.1111/cen.13723 · Cited by 164 · see citing works
Morelli, A., Filippi, S., Comeglio, P., Sarchielli, E., Cellai, I., Pallecchi, M., Bartolucci, G., Danza, G., Rastrelli, G., Corno, C., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00377.2018 · Cited by 59 · see citing works
Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice
Roa, J., Ruiz-Cruz, M., Ruiz-Pino, F., Onieva, R., Vazquez, M. J., Sanchez-Tapia, M. J., Ruiz-Rodriguez, J. M., Sobrino, V., Barroso, A., Heras, V., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32347-4 · Cited by 22 · see citing works
Self-citationBrainstem noradrenergic modulation of the kisspeptin neuron GnRH pulse generator in mice
Vas, S., Morris, P. G., Gul, Z., Ruiz-Cruz, M., Han, S. Y., & Herbison, A. E. (2025) · Nature Communications · doi:10.1038/s41467-025-60837-8 · Cited by 7 · see citing works
- Authors
- Manfredi-Lozano, M., Roa, J., & Tena-Sempere, M.
- Affiliations
- Inserm (FR)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Corresponding author
- Roa, J.
- Venue
- Frontiers in Neuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 48
- Pages
- 37-49
- ISSN
- 0091-3022 (ISSN-L)
- OpenAlex
- W2738559609
- Cited by
- 162
- References
- 15
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 23 · 2023: 22 · 2022: 11 · 2021: 23 · 2020: 15 · 2019: 20 · 2018: 16 · 2017: 3
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Frontiers in Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministerio de Economía y Competitividad (BFU2011-025021, BFU2014-57581-P)
- EU funds
- Instituto de Salud Carlos III, Ministerio de Sanidad (PIE14-00005)
- Junta de Andalucía (P08-CVI-03788, P12-FQM-01943)
- EU research contract DEER (FP7-ENV-2007-1)
- 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 › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- kisspeptin, neurokinin B, POMC neurons, neuropeptide Y, GnRH neurons, hypothalamic-pituitary-gonadal axis, puberty, fertility, energy balance, obesity, gonadal function
- MeSH terms
- Animals, Fertility, Humans, Neuropeptides, Puberty, Reproduction, Sexual Maturation, Signal Transduction, Neurotransmitter Agents
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