Neonatal ghrelin programs development of hypothalamic feeding circuits
Sophie M. Steculorum, … , Sven Klussmann, Sebastien G. Bouret
Sophie M. Steculorum, … , Sven Klussmann, Sebastien G. Bouret
Published January 20, 2015
Citation Information: J Clin Invest. 2015;125(2):846-858. https://doi.org/10.1172/JCI73688.
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Research Article

Neonatal ghrelin programs development of hypothalamic feeding circuits

Abstract

A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation.

Authors

Sophie M. Steculorum, Gustav Collden, Berengere Coupe, Sophie Croizier, Sarah Lockie, Zane B. Andrews, Florian Jarosch, Sven Klussmann, Sebastien G. Bouret

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Figure 1

Ghrelin signaling in neonatal ARH neurons.

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Ghrelin signaling in neonatal ARH neurons. (A) Total plasma ghrelin leve...
(A) Total plasma ghrelin levels and acylated ghrelin levels of P6, P10, P14, and adult mice (n = 6 for P10; n = 5 for P6 and P14; n = 4 for adult). (B) Relative expression of Ghsr mRNA in the ARH of P6, P10, P14, and adult mice (n = 6 for P10; n = 5 for P6 and P14; n = 4 for adult). (C) Circulating acylated ghrelin levels of P6 and P14 mice after a 4-hour fasting (n = 6 per group). (D) Correlation between stomach weight and circulating acylated ghrelin levels in P14 mice (n = 12 per group). (E) Confocal images and quantitative comparisons of pERK+ cells after administration of ghrelin or vehicle alone in P6, P10, P14, and adult mice (n = 5 for P10 and P14; n = 4 for P6 and adult). (F) Confocal images and quantitative comparisons of pERK+ cells after administration of ghrelin or vehicle alone in NPY- and POMC-GFP pups on P10 (n = 4 for vehicle; n = 5 for ghrelin). Arrows point to double-labeled cells. (G) Relative expression of Ghsr mRNA in the brains of P14 mice (n = 4 per group). (H) Quantitative comparisons of pERK+ cells in the brains of P14 mice after administration of ghrelin (n = 4). Values are shown as the mean ± SEM. PmV, ventral premammillary nucleus; SCH, suprachiasmatic nucleus; VMH, ventromedial nucleus; V3, third ventricle. *P < 0.05 vs. P6 and P10 (A); vs. P6, P10, and adult (B); vs. P6 fasted (C); vs. vehicle (E and F); and vs. ARH (G and H). Statistical significance was determined using 2-tailed Student’s t tests (C and F) and a 2-way ANOVA followed by Bonferroni’s post-hoc test (A, B, E, G, and H). Scale bars: 120 μm.