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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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 2

Effects of the anti-ghrelin compound.

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Effects of the anti-ghrelin compound. (A) Representative images of ghrel...
(A) Representative images of ghrelin-induced cFos IR (marker of cellular activation) from P12 and P36 mice neonatally injected with control or anti-ghrelin. (B) Quantitative comparisons of ghrelin-induced cFos IR in the ARH of P12 mice 2, 6, 12, and 24 hours after i.p. administration of control or anti-ghrelin (n = 3 for control; n = 4 for saline and anti-ghrelin). The gray bar shows the number of cFos-IR cells in saline-treated animals. (C) Number of cFos-IR cells of P21 mice neonatally injected with control or anti-ghrelin 2 hours after i.p. administration of ghrelin (2 mg/kg) (n = 3 per group). (D) Stomach content of P14 pups injected with the control or anti-ghrelin compound (n = 7 for control; n = 8 for anti-ghrelin). (E) Relative expression of ghrelin mRNA in the stomachs of P14 pups injected with control or anti-ghrelin (n = 7 per group). (F) Total plasma ghrelin levels of P14 pups injected with control or anti-ghrelin (n = 7 per group). Values are shown as the mean ± SEM. *P < 0.05 vs. control. Statistical significance was determined using 2-tailed Student’s t tests (C–F) and a 2-way ANOVA followed by Bonferroni’s post-hoc test (B). Scale bar: 120 μm.