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  • Review Article
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Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra’s seminal work

Nature Reviews Endocrinology volume 20, pages 111–123 (2024)Cite this article

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Abstract

An individual’s nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra’s trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions.

Key points

  • In 1963, Kennedy and Mitra published a seminal study in rats demonstrating that body weight is a major determinant of pubertal timing.

  • An increasing incidence of earlier ages at puberty has been documented; early pubertal timing favours the occurrence of type 2 diabetes mellitus, cardiovascular diseases and certain cancers in adulthood.

  • Macronutrients and hormones that modulate growth and/or signal adipose tissue mass serve as metabolic cues conveying the nutritional status and stored energy available for sexual maturation, differentiation and growth.

  • The effect of metabolic cues on puberty is mediated by neural targets upstream of GnRH neurons; considerable progress in defining the neuronal circuitry and glial components has been achieved.

  • A number of molecular pathways and epigenetic mechanisms have been identified as primary components in the modulation of pubertal timing by hormones and nutritional cues.

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Fig. 1: Schematic illustration of the neural pathways associated with leptin action in pubertal development in mice.
Fig. 2: Summary of the major signalling pathways engaged by hypothalamic long form of the leptin receptor in pubertal development.

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Acknowledgements

The authors acknowledge the support of the Royal Society of New Zealand #UOO1706 (G.M.A.), of NIH grants R01HD104418 (J.W.H.), R37HD019938, R01HD082314, R21HD098684 (U.B.K.) R01HD090151, R01HD099084, R01DK133760 (V.M.N.), U54AG062322 (V.M.N. and U.B.K.), R01HD069702, R01HD096324 (C.F.E.), from Agencia Estatal de Investigación, Spain PID2020-118660GB-I00; co-funded with EU funds from FEDER Program (M.T.-S.), from the European Commission, Program Horizon Europe HE-ERC-2022-ADG-101096793 (M.T.-S.), the European Union Horizon 2020 research and innovation programme no. 847941 miniNO (V.P.) and no. 810331 WATCH ERC Synergy (V.P.) and the Medical Research Council unit programmes MC_UU_12015/2, MC_UU_00006/2 (J.R.B.P. and K.K.O.).

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Authors and Affiliations

  1. Centre for Neuroendocrinology, University of Otago, Dunedin, New Zealand

    Greg M. Anderson

  2. Department of Anatomy, University of Otago, Dunedin, New Zealand

    Greg M. Anderson

  3. Department of Physiology and Pharmacology, University of Toledo, Toledo, OH, USA

    Jennifer W. Hill

  4. Center for Diabetes and Endocrine Research, University of Toledo, Toledo, OH, USA

    Jennifer W. Hill

  5. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Ursula B. Kaiser & Victor M. Navarro

  6. Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK

    Ken K. Ong & John R. B. Perry

  7. MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK

    John R. B. Perry

  8. University of Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, Lille, France

    Vincent Prevot

  9. European Genomic Institute for Diabetes (EGID), Lille, France

    Vincent Prevot

  10. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain

    Manuel Tena-Sempere

  11. Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain

    Manuel Tena-Sempere

  12. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain

    Manuel Tena-Sempere

  13. Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Carol F. Elias

  14. Department of Obstetrics & Gynecology, University of Michigan, Ann Arbor, MI, USA

    Carol F. Elias

  15. Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, USA

    Carol F. Elias

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  1. Greg M. Anderson
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Contributions

All authors contributed to all aspects of this review.

Corresponding authors

Correspondence to Manuel Tena-Sempere or Carol F. Elias.

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Competing interests

J.R.B.P. is an employee of Insmed Innovation UK, holds stock/stock options in Insmed, and receives research funding from GSK. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks Ei Terasawa, Veronica Mericq and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Anderson, G.M., Hill, J.W., Kaiser, U.B. et al. Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra’s seminal work. Nat Rev Endocrinol 20, 111–123 (2024). https://doi.org/10.1038/s41574-023-00919-z

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