Currently, more than half of all adults in the US, UK and Australia are either overweight or obese. Furthermore, there are increasing rates of being overweight and obesity in all age groups and of concern, women of reproductive age Citation[1–5]. A high maternal BMI increases the risk of developing a series of pregnancy-related complications including gestational diabetes and of giving birth to a large infant (birth weight >4 kg) Citation[6]. While it is not unexpected that the maternal hormonal and nutritional environment would determine fetal nutrient supply and thus the body composition of the newborn infant, it is also known that the effects of the maternal nutritional environment that is experienced in utero persist beyond fetal life. Adult obesity is more prevalent in individuals with birth weights either at the low or high end of the birth weight distribution, such that there is a U-shaped relationship between birth weight and adult fat mass Citation[7]. Thus, heavy mothers have heavier babies, and these babies are more at risk of developing childhood obesity and having a high BMI in later life. Interestingly, recent work in human and experimental cohorts has found that there may be separate contributions of a high maternal BMI at the start of pregnancy and a high maternal weight gain during pregnancy to outcomes such as obesity in childhood Citation[8–10].
It is well established that individuals who grow slowly before birth and rapidly in early childhood have an increased risk of cardiovascular disease (CVD) in adult life Citation[11–14]. What is not yet clear, however, is whether there is also an independent association between growing rapidly before birth and an increased risk of developing CVD. It has been variously reported in studies carried out in historical cohorts that there is an increased risk of CVD at higher birth weights Citation[15], a U-shaped relationship between birth weight and CVD risk after adjustment for adult BMI Citation[16], or that there is an association between childhood BMI and CVD risk which is independent of birth weight Citation[11]. These conflicting findings may relate to the difficulty in separating the impact of maternal BMI at the start of pregnancy and the impact of maternal weight gain during pregnancy to outcomes such as birth weight, body composition and risk of CVD in the offspring in later life.
During the last 5 years, it has become clear that a group of small, conserved RNA molecules of approximately 22 nucleotides (microRNAs or miRs), including miR-1 and -133a, play an essential role in cardiac stem cell differentiation, early heart development and in the adaptive hypertrophic responses of the adult heart to changes in hemodynamic load Citation[17–21]. miRs act as negative modulators of gene expression primarily through base pairing to the 3´ untranslated region of target miRs Citation[21]. Cell cycle withdrawal and multinucleation may be regulated by miRs Citation[22]. The miR-15 family member, miR-195, was identified as the most upregulated miR in cardiomyocytes from mice before and after the transition of the pool of cardiomyocytes from mononucleated and proliferative to multinucleated and nonproliferative. Interestingly, early overexpression of miR-195 in embryonic mouse hearts resulted in smaller hearts with a reduced number of cardiomyocytes in the cell cycle and a higher percentage of multinucleated cardiomyocytes 1 day after birth, suggesting premature cell cycle arrest. Thus, miRs can influence cardiomyocyte endowment by reducing the proliferation of cardiomyocytes in fetal life.
Recent evidence also links a cardiac specific miR that is encoding within an intron of α-myosin heavy chain (α-MHC), miR-208a, to global energy homeostasis. miR208a-/- mice are resistant to high-fat diet-induced obesity, have improved glucose tolerance and insulin sensitivity and appear to be protected from pressure overload-induced cardiac remodeling, including pathological hypertrophy Citation[23]. Further studies suggest that miR-208a inhibition of MED13 is central to the metabolic profile Citation[24], however, an independent mechanism preventing the switch from α-MHC to β-MHC is suggested to protect the heart against pathological hypertrophy.
There is also a miR ‘cluster’ in the heart which includes miR-1 and miR-133a as pairs at different genomic loci, each of which is transcribed as a bicistronic transcript Citation[21]. It has been demonstrated in mice that miR-1 acts to downregulate cardiac IGF1R and IGF1 expression, and that miR-1 and IGF1 levels are inversely related in models of cardiac hypertrophy and heart failure Citation[17,25]. There is also evidence that miR-1 acting through downregulation of the IGF1 signaling pathway decreases phosphorylation of the transcription factor, Foxo-3 Citation[25]. It has also been shown that increased expression of miR-133a in the embryonic heart suppresses cardiomyocyte proliferation and that inhibition of miR-133a in the adult heart results in an increase in heart size. It has been proposed that this hypertrophy may be a consequence of an increase in cell cycling, rather than an increase in cardiomyocyte size Citation[26]. Thus, a decrease in expression of these cardiac specific miRs would result in an increase in IGF1 signaling and proliferation of the cardiomyocytes early in gestation, and potentially in cardiomyocyte hypertrophy. In late gestation in sheep and humans and after birth in rats, growth of the heart then occurs through an increase in the size of these binucleated cardiomyocytes. A range of hormonal and growth factors including angiotensin II, growth hormone, cortisol and IGF-1 have been shown to stimulate cardiomyocyte hyperplasia in fetal hearts Citation[27–29]. In the human and in the sheep, the number of cardiomyocytes present in the adult heart is determined around the time of birth Citation[30,31] and therefore, in cases where this ‘endowment’ of cardiomyocytes is reduced, the remaining cells will be required to increase in size in order to bear a greater share of contractile force generation, with a consequent increase in CVD risk Citation[30,32–34]. There have, to date, been no studies on the impact of exposure of the embryo or fetus to maternal obesity on the expression of miR-1, miR-133a or on the size, type or number of cardiomyocytes present in the fetal or postnatal heart.
Because of the concern about the promulgation of an ‘intergenerational cycle of obesity’, there is significant interest in weight-loss interventions that can be implemented before pregnancy and which improve fertility and pregnancy outcomes in women with a high BMI Citation[35]. However, evidence from experimental studies has shown that maternal weight loss during the periconceptional period may be associated with inadvertent outcomes in the offspring, including an increase in the stress response Citation[10,36], impaired glucose tolerance Citation[37] and blunting of the cardiovascular baroreflex Citation[38]. This suggests that a stronger evidence base is required before recommending specific weight loss regimes in overweight or obese women seeking to become pregnant. Thus, achieving a normal body weight at conception may be critical in determining the final cardiac endowment and thus one’s vulnerability to cardiovascular disease in adult life.
Financial & competing interests disclosure
JL Morrison was supported by a fellowship from the South Australian Cardiovascular Research Network (CR10A4988). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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