Changes in circulating miRNA19a-3p precede insulin resistance programmed by intra-uterine growth retardation in mice

Abstract

Objective Individuals born with intrauterine growth retardation (IUGR) are more prone to cardio-metabolic diseases as adults, and environmental changes during the perinatal period have been identified as potentially crucial factors. We have studied in a preclinical model early-onset molecular alterations present before the development of a clinical phenotype. Methods We used a preclinical mouse model of induced IUGR, in which we modulated the nutrition of the pups during the suckling period, to modify their susceptibility to cardio-metabolic diseases in adulthood. Results Mice born with IUGR that were overfed (IUGR-O) during lactation rapidly developed obesity, hepatic steatosis and insulin resistance, by three months of age, whereas those subjected to nutrition restriction during lactation (IUGR-R) remained permanently thin and highly sensitive to insulin. Mice born with IUGR and fed normally during lactation (IUGR-N) presented an intermediate phenotype and developed insulin resistance by 12 months of age. Molecular alterations to the insulin signaling pathway with an early onset were observed in the livers of adult IUGR-N mice, nine months before the appearance of insulin resistance. The implication of epigenetic changes was revealed by ChIP sequencing, with both posttranslational H3K4me3 histone modifications and microRNAs involved. Conclusions These two changes lead to the coherent regulation of insulin signaling, with a decrease in Akt gene transcription associated with an increase in the translation of its inhibitor, Pten. Moreover, we found that the levels of the implicated miRNA19a-3p also decreased in the blood of young adult IUGR mice nine months before the appearance of insulin resistance, suggesting a possible role for this miRNA as an early circulating biomarker of metabolic fate of potential use for precision medicine.

Epigenetic Mechanisms Responsible for the Transgenerational Inheritance of Intrauterine Growth Restriction Phenotypes

“…Interestingly, higher protein level of PTEN, one of the Akt activation inhibitors, was also found in livers of overfed 3-month-old males. In addition to this, significantly decreased levels of circulating miRNA19a-3p , a miRNA that acts to regulate PTEN, were found in both normally fed and overfed IUGR males ( 93 ). These finding hence suggests an association between altered epigenetic mechanisms and the risk of developing insulin resistance later in life of IUGR offspring.…”

“…Interestingly, a major of the altered miRNAs are predicted to have a common target, which is methyl-CpG binding protein 2 ( 64 ). In a different study where F0 pregnant mice were fed a low-protein/calorie-deficit (-40%) diet from week 3 of gestation, and growth restricted pups were cross-fostered to 3 different groups right after birth, either normal milk feeding (6 pups/dam), overfed (3 pups/dam), or nutrition restriction (10 pups/dam), significantly reduced H3K4me3 (trimethylated histone H3 on lysine 4) region at the Akt1 gene, a gene that is known to play an important role in insulin resistance, was found in livers of 3-month-old IUGR males that either received normal milk feeding or were overfed, in association with reduced expression of Akt1 ( 93 ). Interestingly, higher protein level of PTEN, one of the Akt activation inhibitors, was also found in livers of overfed 3-month-old males.…”

“…These finding hence suggests an association between altered epigenetic mechanisms and the risk of developing insulin resistance later in life of IUGR offspring. Indeed, compared to F1 healthy control males, males that were either under nutrition restriction or overfed both had an increase in sensitivity to insulin at 3 months of age ( 93 ). At 12 months of age, the sensitivity to insulin increased for the nutrition restriction group but attenuated for the overfed group.…”

In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver

“…One such mechanism is miRs, which are small, non-coding RNA molecules that silence target genes through mRNA degradation or repressed protein translation. Numerous miRs have been demonstrated to have aberrant postnatal expression in growth-restricted offspring, leading to cellular stress that precedes impaired function of metabolic organs [ 51 , 86 , 87 , 88 ]. Recent studies found that the translation of p66Shc protein is directly inhibited by miR-203a-3p, leading to the attenuation of liver injury and fibrosis in mice [ 56 ].…”

In Utero Exposure to 9-Tetrahydrocannabinol Leads to Postnatal Catch-up Growth and Dysmetabolism in the Adult Rat Liver

“…One such mechanism is miRs, which are small, non-coding RNA molecules that silence target genes through mRNA degradation or repressed protein translation. Numerous miRs have been demonstrated to have aberrant postnatal expression in growth-restricted offspring, leading to cellular stress that precedes impaired function of metabolic organs [51,[86][87][88]. Recent studies have found that the translation of p66Shc protein is directly inhibited by miR-203a-3p, leading to the attenuation of liver injury and fibrosis in mice [56].…”