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 3

Neonatal ghrelin blockade causes metabolic disturbances.

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Neonatal ghrelin blockade causes metabolic disturbances. (A) Schematic r...
(A) Schematic representation of the experimental design used to specifically block ghrelin action during neonatal life. Starting at P4, pups were treated daily with i.p. injections of the anti-ghrelin compound NOX-B11-2 (15 mg/kg) or an inactive control, for a total of 18 days. (B) Pre- and post-weaning growth curves (body weights) of mice neonatally injected with control or anti-ghrelin compound (n = 8 for control; n = 10 for anti-ghrelin). (C) Body adiposity assessed by MRI at 120 days of age in animals neonatally injected with control or anti-ghrelin (n = 3 for control; n = 4 for anti-ghrelin). (D) The daily food intake of P90 mice neonatally injected with control or anti-ghrelin (n = 6 for control; n = 8 for anti-ghrelin). (E) Plasma leptin and (F) blood glucose levels at 70 days of age in mice neonatally injected with control or anti-ghrelin (n = 6 for control; n = 8 for anti-ghrelin). (G) Leptin sensitivity at 100 days of age in mice neonatally injected with control or anti-ghrelin (n = 5 per group). (H) Glucose tolerance test of P80–P100 mice neonatally injected with control or anti-ghrelin (n = 12 per group). Values are shown as the mean ± SEM. PN, postnatal. *P < 0.05 vs. control or vehicle. Statistical significance was determined using 2-tailed Student’s t tests (C–G) and a 2-way ANOVA followed by Bonferroni’s post-hoc test (B and H).