Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity
Amanda K.E. Hornsby, … , James A. Betts, Timothy Wells
Amanda K.E. Hornsby, … , James A. Betts, Timothy Wells
Published April 1, 2025
Citation Information: J Clin Invest. 2025;135(12):e189202. https://doi.org/10.1172/JCI189202.
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Research Article Endocrinology Metabolism

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

Abstract

The physiological effect of ultradian temporal feeding patterns remains a major unanswered question in nutritional science. We have used 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 with 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 preprandial ghrelin levels in rats, followed by either a sustained elevation in ghrelin in grazing rats or preprandial 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 2 additional bursts of GH per day. Continuous nasogastric infusion of enteral feed in humans failed to suppress circulating ghrelin, producing continuously elevated circulating GH levels with minimal rhythmicity. In contrast, bolus enteral infusion elicited postprandial 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 behavior may be detrimental to optimal skeletal growth outcomes by sustaining circulating ghrelin at levels associated with undernourishment and diminishing GH pulsatility.

Authors

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

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Figure 2

Meal-feeding promotes skeletal growth via a ghrelin-dependent mechanism.

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Meal-feeding promotes skeletal growth via a ghrelin-dependent mechanism....
Cumulative caloric intake (C/I) (A and B), BW gain (C and D), tibia EPW (K), and germinal zone (L), proliferative zone (M), and hypertrophic zone (N) widths (measured in Masson’s trichrome–stained sections in E–J; scale bars: 20 μm), in 6-month-old male ghrelin-KO mice (Ghr-KO) (B, D, and H–J) and their WT male littermates (A, C, and E–G) fed a standard, nonpurified rodent diet (13.9% AFE fat) in either ad libitum–feeding (light gray symbols/bars), grazing (white symbols/bars), or meal-feeding (dark gray symbols/bars) patterns for 3 weeks. Data shown are the mean ± SEM (A–D), with box-and-whisker plots (K–N) showing the median line, mean (+), upper and lower quartile range (bars), data range (whiskers), and individual data points (n = 5, WT grazing, ghrelin-KO grazing; n = 6, WT ad libitum–fed, ghrelin-KO meal-fed; n = 7, WT meal-fed, ghrelin-KO ad libitum–fed). Statistical comparisons were performed by 1-way ANOVA with Bonferroni’s selected-pairs post hoc test. *P < 0.05, **P < 0.01, and ***P < 0.001 versus ad libitum–fed males (same genotype); ††P < 0.01, †††P < 0.001, and ††††P < 0.0001 versus grazing males (same genotype).