Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive

Mihaela Stefan, H. Ji, R. A. Simmons, D. E. Cummings, R. S. Ahima, M. I. Friedman, R. D. Nicholls

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. The syndrome results from loss of function of several clustered, paternally expressed genes in chromosome 15q11-q13. PWS is assumed to result from a hypothalamic defect, but the pathophysiological basis of the disorder is unknown. We hypothesize that a fetal developmental abnormality in PWS leads to the neonatal phenotype, whereas the adult phenotype results from a failure in compensatory mechanisms. To address this hypothesis and better characterize the neonatal failure to thrive phenotype during postnatal life, we studied a transgenic deletion PWS (TgPWS) mouse model that shares similarities with the first stage of the human syndrome. TgPWS mice have fetal and neonatal growth retardation associated with profoundly reduced insulin and glucagon levels. Consistent with growth retardation, TgPWS mice have deregulated liver expression of IGF system components, as revealed by quantitative gene expression studies. Lethality in TgPWS mice appears to result from severe hypoglycemia after postnatal d 2 after depletion of liver glycogen stores. Consistent with hypoglycemia, TgPWS mice appear to have increased fat oxidation. Ghrelin levels increase in TgPWS reciprocally with the falling glucose levels, suggesting that the rise in ghrelin reported in PWS patients may be secondary to a perceived energy deficiency. Together, the data reveal defects in endocrine pancreatic function as well as glucose and hepatic energy metabolism that may underlie the neonatal phenotype of PWS.

Original languageEnglish (US)
Pages (from-to)4377-4385
Number of pages9
JournalEndocrinology
Volume146
Issue number10
DOIs
StatePublished - Oct 2005
Externally publishedYes

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Prader-Willi Syndrome
Failure to Thrive
Phenotype
Ghrelin
Hypoglycemia
Glucose
Hyperphagia
Liver Glycogen
Morbid Obesity
Fetal Growth Retardation
Pediatric Obesity
Liver
Glucagon
Energy Metabolism
Chromosomes
Fats
Insulin
Gene Expression
Growth
Genes

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Stefan, M., Ji, H., Simmons, R. A., Cummings, D. E., Ahima, R. S., Friedman, M. I., & Nicholls, R. D. (2005). Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive. Endocrinology, 146(10), 4377-4385. https://doi.org/10.1210/en.2005-0371

Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive. / Stefan, Mihaela; Ji, H.; Simmons, R. A.; Cummings, D. E.; Ahima, R. S.; Friedman, M. I.; Nicholls, R. D.

In: Endocrinology, Vol. 146, No. 10, 10.2005, p. 4377-4385.

Research output: Contribution to journalArticle

Stefan, M, Ji, H, Simmons, RA, Cummings, DE, Ahima, RS, Friedman, MI & Nicholls, RD 2005, 'Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive', Endocrinology, vol. 146, no. 10, pp. 4377-4385. https://doi.org/10.1210/en.2005-0371
Stefan, Mihaela ; Ji, H. ; Simmons, R. A. ; Cummings, D. E. ; Ahima, R. S. ; Friedman, M. I. ; Nicholls, R. D. / Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive. In: Endocrinology. 2005 ; Vol. 146, No. 10. pp. 4377-4385.
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