Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model

Juan A. Rodriguez, Emily C. Bruggeman, Bharath Kumar Mani, Sherri Osborne-Lawrence, Caleb C. Lord, Henry F. Roseman, Hannah L. Viroslav, Prasanna Vijayaraghavan, Nathan P. Metzger, Deepali Gupta, Kripa Shankar, Claudio Pietra, Chen Liu, Jeffrey M Zigman

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

In the current study, we sought to determine the significance of the ghrelin system in Prader-Willi Syndrome (PWS). PWS is characterized by hypotonia and difficulty feeding in neonates and hyperphagia and obesity beginning later in childhood. Other features include low GH, neonatal hypoglycemia, hypogonadism, and accelerated mortality. Although the hyperphagia and obesity in PWS have been attributed to elevated levels of the orexigenic hormone ghrelin, this link has never been firmly established, nor have ghrelin's potentially protective actions to increase GH secretion, blood glucose, and survival been investigated in a PWS context. In the current study, we show that placing Snord116del mice modeling PWS on ghrelin-deficient or ghrelin receptor [GH secretagogue receptor (GHSR)]-deficient backgrounds does not impact their characteristically reduced body weight, lower plasma IGF-1, delayed sexual maturation, or increased mortality in the period prior to weaning. However, blood glucose was further reduced in male Snord116del pups on a ghrelin-deficient background, and percentage body weight gain and percentage fat mass were further reduced in male Snord116del pups on a GHSR-deficient background. Strikingly, 2 weeks of daily administration of the GHSR agonist HM01 to Snord116del neonates markedly improved survival, resulting in a nearly complete rescue of the excess mortality owing to loss of the paternal Snord116 gene. These data support further exploration of the therapeutic potential of GHSR agonist administration in limiting PWS mortality, especially during the period characterized by failure to thrive.

Original languageEnglish (US)
Pages (from-to)4006-4022
Number of pages17
JournalEndocrinology
Volume159
Issue number12
DOIs
StatePublished - Dec 1 2018

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Ghrelin Receptor
Prader-Willi Syndrome
Infant Mortality
Ghrelin
Mortality
Hyperphagia
Blood Glucose
Obesity
Body Weight
Sexual Maturation
Failure to Thrive
Muscle Hypotonia
Hypogonadism
Weaning
Insulin-Like Growth Factor I
Hypoglycemia
Weight Gain
Fats
Hormones
Genes

ASJC Scopus subject areas

  • Endocrinology

Cite this

Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model. / Rodriguez, Juan A.; Bruggeman, Emily C.; Mani, Bharath Kumar; Osborne-Lawrence, Sherri; Lord, Caleb C.; Roseman, Henry F.; Viroslav, Hannah L.; Vijayaraghavan, Prasanna; Metzger, Nathan P.; Gupta, Deepali; Shankar, Kripa; Pietra, Claudio; Liu, Chen; Zigman, Jeffrey M.

In: Endocrinology, Vol. 159, No. 12, 01.12.2018, p. 4006-4022.

Research output: Contribution to journalArticle

Rodriguez, JA, Bruggeman, EC, Mani, BK, Osborne-Lawrence, S, Lord, CC, Roseman, HF, Viroslav, HL, Vijayaraghavan, P, Metzger, NP, Gupta, D, Shankar, K, Pietra, C, Liu, C & Zigman, JM 2018, 'Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model', Endocrinology, vol. 159, no. 12, pp. 4006-4022. https://doi.org/10.1210/en.2018-00801
Rodriguez JA, Bruggeman EC, Mani BK, Osborne-Lawrence S, Lord CC, Roseman HF et al. Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model. Endocrinology. 2018 Dec 1;159(12):4006-4022. https://doi.org/10.1210/en.2018-00801
Rodriguez, Juan A. ; Bruggeman, Emily C. ; Mani, Bharath Kumar ; Osborne-Lawrence, Sherri ; Lord, Caleb C. ; Roseman, Henry F. ; Viroslav, Hannah L. ; Vijayaraghavan, Prasanna ; Metzger, Nathan P. ; Gupta, Deepali ; Shankar, Kripa ; Pietra, Claudio ; Liu, Chen ; Zigman, Jeffrey M. / Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model. In: Endocrinology. 2018 ; Vol. 159, No. 12. pp. 4006-4022.
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AU - Lord, Caleb C.

AU - Roseman, Henry F.

AU - Viroslav, Hannah L.

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AU - Metzger, Nathan P.

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AU - Pietra, Claudio

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