Disruption of theIgf2gene alters hepatic lipid homeostasis and gene expression in the newborn mouse

Abstract

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long co-morbidities. 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 up-regulated gene - serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also up-regulated. 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 perixosome 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.

Early-life exposure to severe famine is associated with higher methylation level in the IGF2 gene and higher total cholesterol in late adulthood: the Genomic Research of the Chinese Famine (GRECF) study

“…Although further studies are needed to validate the finding in an independent Chinese sample, our study together with the Dutch famine studies indicates that the IGF2 gene is important in lipid metabolism in human. The finding is supported by a recent study among mice, which demonstrated that Igf2 knockout mice displayed altered expression levels of genes involved in lipid and fatty acid metabolisms [25]. Early-life nutrition supply, development and growth, and lipids in adulthood warrant further investigation.…”

“…The IGF2 gene encodes insulin-like growth factor II and plays a key role in human development and growth. Animal studies revealed that lgf2 knockout mice mimicked nutritional deficiency in utero and resulted in growth restriction and neonatal glycogen stores reduction [25]. The gene is maternally imprinted and paternally expressed [26–28], and methylation changes in the gene persist until at least middle age [29].…”

“…The IGF2 per se is involved in lipid metabolism. Animal studies identified that disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in mice [25]. Negative feedback loop regulation of lipids on IGF2 expression has not been reported.…”

Expression of genes encoding IGF1, IGF2, and IGFBPs in blood of obese adolescents with insulin resistance

“…Moreover, insulin-like growth factor 2 expression in prostate cancer is regulated by promoter-specific methylation (Kuffer et al 2018). Disruption of this gene alters hepatic lipid homeostasis and gene expression in the newborn mouse (Lopez et al 2018).…”

Beneficial effects of an endogenous enrichment in n3‐PUFAs on Wnt signaling are associated with attenuation of alcohol‐mediated liver disease in mice

“…Oil Red O staining was performed as described previously, with minor modifications. 22 Cryosections were incubated with 0.5% (w/v) Oil Red O in propylene glycol (Electron Microscopy Sciences, Hadfield, PA) at 60°C for 10 minutes. Staining was quantified by imaging 10 random fields/section (200× magnification), and then measuring Oil Red O-positive areas using a macro written in Image J.…”