Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity

Amanda K.E. Hornsby; Richard C. Brown; Thomas W. Tilston; Harry A. Smith; Alfonso Moreno-Cabañas; Bradley Arms-Williams; Anna L. Hopkins; Katie D. Taylor; Simran K.R. Rogaly; Lois H.M. Wells; Jamie J. Walker; Jeffrey S. Davies; Yuxiang Sun; Jeffrey M. Zigman; James A. Betts; Timothy Wells

doi:10.1172/JCI189202

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Hornsby, A. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Brown, R. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Tilston, T. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Smith, H. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Moreno-Cabañas, A. in: JCI | PubMed | Google Scholar |

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Arms-Williams, B. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Hopkins, A. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Taylor, K. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Rogaly, S. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Wells, L. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Walker, J. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Davies, J. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Sun, Y. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Zigman, J. in: JCI | PubMed | Google Scholar |

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Betts, J. in: JCI | PubMed | Google Scholar

¹School of Biosciences, Cardiff University, Cardiff, United Kingdom

²Centre for Nutrition, Exercise & Metabolism, Department for Health, University of Bath, Bath, United Kingdom

³Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom

⁴Institute of Life Sciences, School of Medicine, Swansea University, Swansea, United Kingdom

⁵Department of Nutrition, Texas A&M University, College Station, United States of America

⁶UT Southwestern Medical Center, Dallas, United States of America

Find articles by Wells, T. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI189202.
Copyright © 2025, Hornsby et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 1, 2025 - Version history

The physiological impact of ultradian temporal feeding patterns remains a major unanswered question in nutritional science. We have employed automated and nasogastric feeding to address this question in male rodents and human volunteers. While grazing and meal-feeding reduced food intake in parallel (compared to ad libitum-fed rodents), body length and tibial epiphysial plate width were maintained in meal-fed rodents via the action of ghrelin and its receptor, GHS-R. Grazing and meal-feeding initially suppressed elevated pre-prandial ghrelin levels in rats, followed by either a sustained elevation in ghrelin in grazing rats or pre-prandial ghrelin surges in meal-fed rats. Episodic growth hormone (GH) secretion was largely unaffected in grazing rats, but meal-feeding tripled GH secretion, with burst height augmented and two additional bursts of GH per day. Continuous nasogastric infusion of enteral feed in humans failed to suppress circulating ghrelin, producing continuously elevated circulating GH with minimal rhythmicity. In contrast, bolus enteral infusion elicited post-prandial ghrelin troughs accompanied by reduced circulating GH, with enhanced ultradian rhythmicity. Taken together, our data imply that the contemporary shift from regular meals to snacking behaviour may be detrimental to optimal skeletal growth outcomes by sustaining circulating GH at levels associated with undernourishment and diminishing GH pulsatility.

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Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity

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