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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.

SUBMITTER: Steculorum SM

PROVIDER: S-EPMC4319433 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Neonatal ghrelin programs development of hypothalamic feeding circuits.

Steculorum Sophie M SM Collden Gustav G Coupe Berengere B Croizier Sophie S Lockie Sarah S Andrews Zane B ZB Jarosch Florian F Klussmann Sven S Bouret Sebastien G SG

The Journal of clinical investigation 20150120 2

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 postnat ...[more]

PMID: 25607843

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Project description:ObjectiveGhrelin is a stomach-derived hormone that affects food intake and regulates blood glucose. The best-characterized actions of ghrelin are mediated by its binding to and activation of the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Adequate examination of the identity, function, and relevance of specific subsets of GHSR-expressing neurons has been hampered by the absence of a suitable Cre recombinase (Cre)-expressing mouse line with which to manipulate gene expression in a targeted fashion within GHSR-expressing neurons. The present study aims to characterize the functional significance and neurocircuitry of GHSR-expressing neurons in the mediobasal hypothalamus (MBH), as they relate to ghrelin-induced food intake and fasting-associated rebound hyperphagia, using a novel mouse line in which Cre expression is controlled by the Ghsr promoter.MethodsA Ghsr-IRES-Cre mouse line that expresses Cre directed by the Ghsr promoter was generated. The line was validated by comparing Cre activity in reporter mice to the known brain distribution pattern of GHSR. Next, the requirement of MBH GHSR-expressing neuronal activity in mediating food intake in response to administered ghrelin and in response to fasting was assessed after stereotaxic delivery of inhibitory designer receptor exclusively activated by designer drugs (DREADD) virus to the MBH. In a separate cohort of Ghsr-IRES-Cre mice, stereotaxic delivery of stimulatory DREADD virus to the MBH was performed to assess the sufficiency of MBH GHSR-expressing neuronal activity on food intake. Finally, the distribution of MBH GHSR-expressing neuronal axonal projections was assessed in the DREADD virus-injected animals.ResultsThe pattern of Cre activity in the Ghsr-IRES-Cre mouse line mostly faithfully reproduced the known GHSR expression pattern. DREADD-assisted inhibition of MBH GHSR neuronal activity robustly suppressed the normal orexigenic response to ghrelin and fasting-associated rebound food intake. DREADD-assisted stimulation of MBH GHSR neuronal activity was sufficient to induce food intake. Axonal projections of GHSR-expressing MBH neurons were observed in a subset of hypothalamic and extra-hypothalamic regions.ConclusionsThese results suggest that 1) activation of GHSR-expressing neurons in the MBH is required for the normal feeding responses following both peripheral administration of ghrelin and fasting, 2) activation of MBH GHSR-expressing neurons is sufficient to induce feeding, and 3) axonal projections to a subset of hypothalamic and/or extra-hypothalamic regions likely mediate these responses. The Ghsr-IRES-Cre line should serve as a valuable tool to further our understanding of the functional significance of ghrelin-responsive/GHSR-expressing neurons and the neuronal circuitry within which they act.

Project description:The benefits of school feeding have been well documented. As such, school feeding programs have continuously gained popularity in developing countries. However, challenges and potential opportunities persist, calling for a review of school feeding for long-term sustainability. South Africa has an opportunity to improve their National School Nutrition Program (NSNP) by including an energy-dense snack that would increase the recommended dietary allowance (RDA) of school children to meet at least 25% of their energy requirements. The objective of this scoping review was to conduct a review and an appraisal of studies on snack food development for school feeding programs in Africa. Eligible studies had to report snack development for school feeding programs in Africa. We conducted an electronic search in National Research Foundation (NRF) NEXUS, Elton B. Stephens Company (EBSCO), International Food Information Service (IFIS), Nutrition and Food Sciences Center for Agriculture and Bioscience International (CABI.ORG), and Google Scholar. Of the 429 articles identified, nine studies were included in the final review-five from within South Africa and four from elsewhere in Africa. Data extracted included the study design, intervention, outcomes, relevant findings, and limitations. Results were presented in a narrative summary. The review findings showed that energy-rich staple foods and food fortification were commonly used in snack development. The popular snack products developed included porridges and biscuits. While most studies reported nutritional outcomes, few studies reported on sensory acceptability tests and only two studies conducted a cost analysis. This review of previous snack development initiatives for school feeding programs in Africa underscores the importance of establishing the sustainability of any food product developed. The findings of this review have the potential to inform future snack product development for school feeding programs.

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Neonatal ghrelin programs development of hypothalamic feeding circuits.

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Neonatal ghrelin programs development of hypothalamic feeding circuits.

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