Abstract
Fetal programming refers to an intrauterine stimulus or insult that shapes growth, development and health outcomes. Dependent on the quality and quantity, dietary fats can be beneficial or detrimental for the growth of the fetus and can alter insulin signaling by regulating the expression of key factors. The effects of varying dietary fat content on the expression profiles of factors in the neonatal female and male rat heart were investigated and analyzed in control (10% fat), 20F (20% fat), 30F (30% fat) and 40F (40% fat which was a high fat diet used to induce high fat programming) neonatal rats. The whole neonatal heart was immunostained for insulin receptor, glucose transporter 4 (Glut4) and forkhead box protein 1 (FoxO1), followed by image analysis. The expression of 84 genes, commonly associated with the insulin signaling pathway, were then examined in 40F female and 40F male offspring. Maintenance on diets, varying in fat content during fetal life, altered the expression of cardiac factors, with changes induced from 20% fat in female neonates, but from 30% fat in male neonates. Further, CCAAT/enhancer-binding protein alpha (Cebpa) was upregulated in 40F female neonates. There was, however, differential expression of several insulin signaling genes in 40F (high fat programmed) offspring, with some tending to significance but most differences were in fold changes (≥1.5 fold). The increased immunoreactivity for insulin receptor, Glut4 and FoxO1 in 20F female and 30F male neonatal rats may reflect a compensatory response to programming to maintain cardiac physiology. Cebpa was upregulated in female offspring maintained on a high fat diet, with fold increases in other insulin signaling genes viz. Aebp1, Cfd (adipsin), Adra1d, Prkcg, Igfbp, Retn (resistin) and Ucp1. In female offspring maintained on a high fat diet, increased Cebpa gene expression (concomitant with fold increases in other insulin signaling genes) may reflect cardiac stress and an adaptative response to cardiac inflammation, stress and/or injury, after high fat programming. Diet and the sex are determinants of cardiac physiology and pathophysiology, reflecting divergent mechanisms that are sex-specific.
Highlights
Fetal programming is defined as the predisposition of the fetus to metabolic abnormalities due to stimuli or insults during critical developmental phases
30% fat (30F) and 40% fat (40F) female neonates had reduced insulin receptor immunoreactivity compared to 20% fat (20F) female neonates (Figure 1A)
20F and 30F females showed higher Glucose transporter 4 (Glut4) immunoreactivity compared to the control and 40F females
Summary
Fetal programming is defined as the predisposition of the fetus to metabolic abnormalities due to stimuli or insults during critical developmental phases. Insulin resistance, which is closely associated with obesity, predisposes to cardiovascular disease, diabetes and metabolic syndrome [2, 3] – pathologies that contribute greatly to global morbidity and mortality [4]. A maternal HFD and/or maternal gestational obesity contribute to the origin of metabolic disease in the offspring, are associated with congenital abnormalities, and may increase neonatal morbidity and mortality [9] with gestational HFDs adversely affecting the offspring’s metabolic physiology [10]. Maternal gestational obesity predisposes offspring to diabetes, insulin resistance and hyperinsulinemia [11, 12]. The compromised maternal metabolic milieu exposes the developing fetus to elevated glucose and lipids, that stimulate fetal hyperinsulinemia and adversely affect the developing fetal heart [16]. In offspring from mothers with diabetic pregnancies, maintenance on a HFD further impaired diastolic and systolic function through oxidative stress, mitochondrial dysfunction, the accumulation of lipid droplets and metabolic derangements [16]
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