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Am J Physiol Endocrinol Metab. 2018 Nov 1;315(5):E735-E744. doi: 10.1152/ajpendo.00048.2018. Epub 2018 Jul 17.

Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse.

Author information

1
Center for Basic and Translational Obesity Research , Boston, Massachusetts.
2
Endocrine Division, Boston Children's Hospital , Boston, Massachusetts.
3
Harvard Medical School , Boston, Massachusetts.
4
The Harvard Clinical and Translational Science Center and Countway Library of Medicine , Boston, Massachusetts.

Abstract

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type ( Igf2+/+) littermates, brain size was preserved in Igf2 knockout ( Igf2-/-), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2-/- mice are born with hepatic steatosis. Gene expression analysis in Igf2-/- newborn livers showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most upregulated gene, serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also upregulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2-/- newborns are related to lipid metabolism, with the top upstream regulator predicted to be the peroxisome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn.

KEYWORDS:

Igf2; lipid; liver; newborn; serine dehydratase

PMID:
30016152
PMCID:
PMC6293172
DOI:
10.1152/ajpendo.00048.2018
[Indexed for MEDLINE]

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