Epigenetics and Programming

Epigenetics is a genetic process that switches genes on and off in response to external or environmental factors. The essential concept of “gestational programming” signifies that the nutritional, hormonal, and metabolic environment provided by the mother permanently alters organ structure, cellular responses, and gene expression that ultimately impact the metabolism and physiology of her offspring ( Fig. 5-1 ). Further, these effects vary and are dependent upon the developmental period, and as such, rapidly growing fetuses and neonates are more vulnerable. The programming events may have immediate effects—for example, impairment of organ growth at a critical stage—whereas other programming effects are deferred until expressed by altered organ function at a later age. In this instance, the question is about how the memory of early events is stored and later expressed despite continuous cellular replication and replacement. This may be mediated through epigenetic control of gene expression, which involves modification of the genome without altering the DNA sequence.

Impact of gestational programming on organ systems.

Epigenetic phenomena are fundamental features of mammalian development that cause heritable and persistent changes in gene expression without altering DNA sequence. Epigenetic regulation includes changes in the DNA methylation pattern and modifications of chromatin packaging via posttranslational histone changes.

DNA methylation represents a primary epigenetic mechanism. The DNA of the early embryo is hypomethylated, and with progressive increases in DNA methylation in response to environmental signals, organogenesis and tissue differentiation occur. DNA methylation typically occurs on cytosine bases that are followed by a guanine, termed CpG dinucleotides. The methylation by a DNA methyltransferase leads to recruitment of methyl-CpG binding proteins, which induce transcriptional silencing both by blocking transcription factor binding and by recruiting transcriptional corepressors or histone-modifying complexes. Anomalous DNA methylation in normally hypomethylated CpG-rich regions of gene promoters is associated with inappropriate gene silencing (e.g., cancer). It is during embryogenesis and early postnatal life that DNA methylation patterns are fundamentally established and are imperative for silencing of specific gene regions, such as imprinted genes and repetitive nucleic acid sequences. The epigenome is reestablished at specific stages of development, making it a prime candidate as the basis for fetal programming. As such, changes in epigenetic markers are associated with inflammation and multiple human diseases, including many cancers and neurologic disorders. Because methylation requires the nutrient supply and enzymatic transfer of methyl groups, it is plausible that in utero nutritional, hormonal, or other metabolic cues alter the timing and direction of methylation patterns during fetal development ( Fig. 5-2 ).

DNA methylation. A, Methylation by DNA methyltransferases at CpG islands. B, DNA demethylation relaxes chromatin structure, which allows histone acetylation and the binding of transcriptional complexes.

Another essential mechanism of gene expression and silencing is the packaging of chromatin into open (euchromatic) or closed (heterochromatic) states, respectively. Chromatin consists of DNA packaged around histones into a nucleoprotein complex. Posttranslational modification of histone tails through acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation can alter histone interaction with DNA and recruit proteins (e.g., transcriptional factors) that alter chromatin conformation. Histone tail acetylation by histone acetyltransferases promotes active gene expression, whereas histone tail deacetylation by histone deacetylases (HDACs) is associated with gene silencing ( Fig. 5-3 ). Histone methylation can either repress or activate transcription depending on which lysine is methylated. For example, trimethylation of histone H3 at lysine 4 (H3K4me3) is associated with active gene transcription, whereas dimethylation of histone H3 at lysine 9 (H3K9me2) is associated with transcriptional silencing. Histone modifications and DNA methylation patterns are not exclusively independent, and thus they can reciprocally regulate one another’s state.

DNA methylation, histone modification, and noncoding RNA.

Finally, noncoding RNAs (ncRNAs) are emerging as a potential third epigenetic mediator. The ncRNAs are transcribed from DNA but are not translated into proteins, and they function to regulate gene expression at the transcriptional and posttranscriptional level. The three major short ncRNAs (<30 nucleotides) associated with gene silencing are micro­RNAs (miRNAs), short inhibitory RNAs (siRNAs), and piwi-interacting RNAs (piRNAs). Long ncRNAs (>200 nucleotides) play a regulatory role during development and exhibit cell type–specific expression. Whereas these ncRNAs are usually associated with regulation of gene expression at the translational level, recent work suggests they may be involved in DNA methylation as well, thereby further regulating transcription of their targets.

Both human and animal studies provide evidence of epigenomic modulation by the maternal milieu; importantly, they implicate it in the transmission of gestational programming effects to multiple generations.

Fetal Nutrition and Growth

Nutrition is unquestionably one of the cornerstones of health. More importantly, good evidence suggests that appropriate nutritional supplementation before conception and during pregnancy may reduce the risk of some birth defects (see Chapters 6 and 7 ). Perhaps the most convincing argument that can be made for the need to consider maternal nutrition as a critical modulator of embryonic development is the observation that maternal iodine supplementation has eradicated the occurrence of iodine deficiency–induced cretinism and other iodine deficiency–associated developmental defects. In addition, adverse maternal nutrition—which has an immediate and visible impact on the outcome of pregnancy—is seen in the case of folate deficiency and spina bifida. Similarly, maternal polymorphisms in the genes of folate metabolism are also associated with intrauterine growth restriction (IUGR) and abnormalities that include cleft palate and heart defects. In addition to its critical role in the conversion of homocysteine to methionine, the functional mechanism for folate likely involves epigenetic effects, because folate generates the principal methyl donor (s-adenosyl methionine [SAMe]) that participates in methylation of DNA and histones.

Animal studies have also irrevocably shown the importance of a mother’s diet in shaping the epigenome of her offspring. A classic example is that of permanent hypomethylation of certain regions of the genome as a result of deficient folate or choline (methyl donors) during late fetal or early postnatal life. Specifically, in viable yellow agouti mice, when the agouti gene is completely unmethylated, the mouse has a yellow coat color and is obese and prone to diabetes and cancer. When the agouti gene is methylated, as in normal mice, the coat color is brown and the mouse has a low disease risk. Although both the fat yellow and skinny brown mice are genetically identical, the former exhibits an epigenetic “mutation.”

Although teratogenesis, structural malformations, and even onogenic risks can be linked to developmental insults, it is only recently that the epidemic of metabolic syndrome has been attributed, in part, to consequences of fetal and newborn development. Obesity now represents a major public health problem and health epidemic (see Chapter 41 ). As recently reported, the adverse consequences of obesity are projected to overwhelm the beneficial effects of reduced smoking in the United States and have resulted in an actual decline in life expectancy. In the United States, 69% of adults are overweight (body mass index [BMI] from 25 to 30 kg/m ² ), and 35% are obese (BMI ≥30 kg/m ² ). Of concern to obstetricians is a marked and continuing increase in the prevalence of obesity among pregnant women, a factor associated with both obstetric complications and high-birthweight newborns, a known risk factor for childhood obesity. Whereas the epidemic of obesity in the United States was originally attributed to changes in the work environment, a surplus of high calories, inexpensive food, and a lack of childhood exercise, it is now recognized that the risks of obesity in metabolic syndrome can be markedly influenced by early life events, particularly prenatal and neonatal growth and environmental exposures. In the early 1990s, Barker and Hales brought attention to this with epidemiologic studies demonstrating that nutritional insufficiency during embryonic and fetal development resulted in latent disease, including obesity, in adulthood. A series of studies have demonstrated a marked increase in deaths from coronary heart disease and adult hypertension in association with small for gestational age (SGA) newborns. In addition, investigators observed impaired glucose tolerance and diabetes in association with LBW.

Whereas the incidence of growth restriction has risen in the United States due in part to medical complications such as hypertension and multiple gestations, an approximate 25% increase in the incidence of high-birthweight (HBW) babies has also been seen during the past decade. Epidemiologic studies have confirmed that the relationship between birthweight and adult obesity, cardiovascular disease, and insulin resistance is in fact a U-shaped curve, with increasing risks at both the low and high ends of the birthweight spectrum. Importantly, the sequelae of programming do not occur as a threshold response associated with either very low or very high birthweight, rather they represent a continuum of risk for adult disease in relation to variance from an ideal newborn birthweight.

As will be described below, these studies have spawned a burst of epidemiologic and mechanistic studies of the developmental origins of adult diseases. The original focus on cardiovascular disease and metabolic syndrome has been extended to a diversity of adult diseases—including cancer and diseases that affect the kidneys, lungs, and immune system—and also with learning ability, mental health, and aging. Thus the field of developmental origins of adult disease has grown from considering short-term toxic or teratogenic effects to looking at long-term adult sequelae of low or high birthweight and, more recently, at the impact of environmental toxins (e.g., bisphenol A [BPA]). In addition to these influences, other factors that include maternal stress, preterm delivery, and maternal glucocorticoid therapy, among others, may significantly impact adult health and disease.

Energy-Balance Programming

As noted above, epidemiologic studies demonstrate that the metabolic syndrome —a cluster of conditions that include obesity, hypertension, dyslipidemia, and impaired glucose tolerance—may be a result in part of the effects of LBW. Ultimately, obesity results from an imbalance in energy intake and expenditure as regulated by appetite, metabolism, adipogenic propensity, and energy utilization. In 1992, Hales and Barker proposed the “thrifty phenotype hypothesis” and suggested that in response to an impaired nutrient supply in utero, the growing fetus adapts to maximize metabolic efficiency because it will increase survival likelihood in the postnatal environment. This adaptation would be beneficial in response to environmental cycles of famine and drought, in which reduced maternal—and thus fetal—nutrient supply would likely be replicated in the subsequent extrauterine environment. Numerous studies have demonstrated the increased risk of obesity associated with LBW. In addition to obesity, LBW appears to predispose to excess central adiposity, a phenotype specifically associated with risk for cardiovascular disease.

Although the long-term effects of LBW are linked to adult obesity, several studies have demonstrated important effects of newborn or childhood catch-up growth among the LBW infants. Those infants who are born small and remain small in comparison to their peers exhibit a lower risk of obesity and metabolic syndrome than those born small who catch up and exceed normal weights through infancy or early adolescence. These findings, replicated in animal models, have great significance for neonatal and childhood care. For example, a major goal of the treatment for premature LBW infants is the achievement of a minimum weight satisfactory for hospital discharge at birth. Contrary to current practice, it may be advisable to limit rapid weight gain in the neonatal period. Importantly, breastfeeding results in a lower obesity risk compared with formula feeding. Breastfeeding may have advantages over formula feeding in both nutrient and hormone composition as well as in the natural limitations that prevent overfeeding.

As discussed above, programming effects of birthweight simulate a U-shaped curve because LGA infants also are at an increased risk of adult cardiovascular disease and diabetes. Understandably, LGA infants are often born to obese women, who frequently express glucose intolerance or insulin resistance and who often consume high-fat Western diets prior to and throughout pregnancy. Studies demonstrate that each of these risks— obesity, glucose intolerance, and a high-fat diet—and their outcomes (LGA) may individually contribute to the programming of adult obesity. When combined with variations in maternal feeding and different childhood diets, it is understandable that epidemiologic studies have not yet determined which of these factors is paramount in programming mechanisms. As discussed below, animal models demonstrate programming effects independently associated with each of these risks.

Animal models of LBW that have used a variety of methods—such as maternal nutrient restriction (global or specific), uterine artery ligation, and glucocorticoid exposure, among others—have effectively demonstrated increased adult adiposity. Similar to human studies, the propensity to obesity is particularly evident in LBW newborns who exhibit postnatal catch-up growth. Studies primarily on rodents and sheep have provided important insights into the underlying mechanisms of programmed obesity, which include lasting changes in proportions of fat and lean body mass, central nervous system appetite control, adiposity structure and function, adipokine secretion and regulation, and energy expenditure.

Animal models of overnutrition mimic the modern dietary intake of high-fat, high-carbohydrate diets. Maternal obesity and high-fat, high-carbohydrate diets also result in increased adult programmed adiposity, notably via mechanisms that impact appetite and adipose tissue.

Programming by Environmental Agents

Increasing human exposure to a wide range of industrial and agricultural chemicals has been well recognized. The Centers for Disease Control and Prevention (CDC) reported significant human exposure to endocrine-disrupter chemicals (EDCs), including those that act via estrogen receptors (eEDCs). BPA is a nearly ubiquitous monomer plasticizer. The consistent findings of elevated BPA levels indicates continued routine exposure of adults and children. BPA is measurable in breast milk (1.1 ng/mL), maternal (1 to 2 ng/mL) and fetal serum (0.2 to 9.2 ng/mL), amniotic fluid (8.3 to 8.7 ng/mL), and placental tissues (1.0 to 104.9 ng/mL; Fig. 5-4 ). BPA pharmacokinetics are similar in women, female monkeys, and rodents. BPA metabolism includes conjugation and clearance as BPA-glucuronide and BPA-sulfate, with most BPA found recovered in urine. Because the fetus and newborn have reduced conjugation capacity, BPA elimination is likely prolonged. Furthermore, the well-documented fetal swallowing of amniotic fluid recirculates BPA excreted in fetal urine. These findings explain, in part, the elevated fetal serum and amniotic fluid BPA levels.

Bisphenol A levels during pregnancy.

Higher BPA urinary concentrations are associated with increased adiposity at 9 years of age, and BPA levels are associated strongly with levels of the adipokines adiponectin and leptin. Thus BPA exposure and maternal obesity may act synergistically to program obesity in the offspring. Epidemiologic studies support the association of human developmental EDC exposure and obesity in later life. Prenatal and early life polychlorinated biphenyl (PCB) exposure is associated with increased male and female weight at puberty. In utero exposure to hexachlorobenzene is linked to overweight children at age 6 years, and organochlorine pesticides are positively associated with BMI.

The programming effects of BPA exposure are likely diverse; human epidemiologic studies have associated maternal BPA urinary concentrations with hyperactivity, aggression, anxiety, and depression, with effects more apparent in female offspring. Among inner-city children, prenatal BPA exposure is linked to altered emotional behavior such that males were more aggressive and females were less anxious or depressed.

Animal models of BPA exposure indicate that BPA-programmed obesity mechanisms include changes in adipogenesis and neurogenesis. In vitro studies reveal marked embryologic effects of BPA that include alterations in cell differentiation. The proadipogenic effects of environmental obesogens have been well documented; recent studies have demonstrated effects on adipocyte generation that resulted in an increased number, differentiation, and lipogenic function with potential epigenetic effects that traverse generations. In rats, prenatal BPA increased adipogenesis in females at weaning in association with overexpression of several lipogenic genes ( C/EBPα, PPARγ, SREBP1 , lipoprotein lipase, fatty acid synthase, and stearoyl-CoA desaturase-1). In samples from children, low-dose BPA increased the mRNA expression and enzymatic activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in omental adipose tissue and visceral adipocytes, consistent with BPA-induced acceleration of adipogenesis. At environmentally relevant doses, BPA inhibits adiponectin and stimulates release of inflammatory adipokines, including interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) from human adipose tissue.

In addition to adipogenic effects, recent EDC studies indicate neurodevelopmental effects of BPA. Low-dose maternal BPA exposure has been shown to accelerate neurogenesis and neuronal migration in mice and results in aberrant neuronal network formation. As a consequence of accelerated neurogenesis, maternal BPA reduces the fetal neural stem/progenitor cell population at embryonic day 14.5. Maternal BPA exposure may ultimately program offspring appetite development; BPA upregulates critical mouse embryonic genes associated with appetite pathway neurogenesis, and in vitro BPA stimulates proliferation of neuroprogenitor cells.

BPA effects have been demonstrated both histologically and behaviorally. Prenatal and neonatal BPA exposure induces dysfunction of the hippocampal cholinergic system. Prenatal BPA may also alter development of dopamine and N-methyl-D-aspartate (NMDA) systems in association with offspring anxious behaviors and cognitive deficits as well as serotoninergic systems that regulate mood. Gender-specific effects are well documented; in utero BPA exposure has been found to alter offspring rat brain structure and behavior, including sexually dimorphic behaviors, with effects more apparent in females than in males. Male mice offspring demonstrated increased aggression and memory impairment in addition to increased brain expression of estrogen receptors alpha and beta during early life. In studies of primates, prenatal BPA was found to alter male cynomolgus monkey offspring sexual behavior. As noted earlier, these effects have been identified in human offspring as well.

Mechanisms of Programmed Obesity: Appetite and Adiposity

The hypothalamic regulation of appetite and satiety function develops in utero in precocial species, those in which the young are relatively mature as newborns. In the rat and in humans, although neurons that regulate appetite and satiety become detectable in the fetal hypothalamus early in gestation, the functional neuronal pathways form during the second week of postnatal life in the rat and likely during the third trimester in humans. Notably, the obesity gene product leptin, which is synthesized primarily by adipose tissue and the placenta, is a critical neurotrophic factor during development. In contrast to the adult, in which leptin acts as a satiety factor, fetal/neonatal leptin promotes the development of satiety pathways. In leptin-deficient (ob/ob) mice, satiety pathways are permanently disrupted and demonstrate axonal densities one third to one fourth that of controls. Treatment of adult ob/ob mice with leptin does not restore satiety projections, but leptin treatment of newborn ob/ob mice does rescue the neuronal development, indicating the critical role of leptin during the perinatal period.

Early-life leptin exposure is likely a putative programming mechanism in SGA and LGA human newborns. In LBW human offspring, leptin levels are low at delivery, and cord blood levels reflect neonatal fat mass. In contrast to the low serum levels of leptin in SGA newborns, LGA infants have elevated leptin levels. Obese pregnant mothers further have elevated leptin levels related to maternal adiposity, and breast milk leptin levels also reflect maternal fat mass.

Leptin binding to its receptor activates proopiomelanocortin (POMC) neurons and downstream anorexigenic pathways. Obesity is often associated with leptin resistance, which results in an inability to balance food intake with actual energy needs. The leptin pathway is counterregulated by the orexigenic neuropeptide Y (NPY; Fig. 5-5 ). Impaired leptin signaling could result in increased expression of NPY, which would promote increased nutrient intake while decreasing overall physical activity. In LBW newborns, appetite dysregulation has been demonstrated as a key predisposing factor for the obese phenotype. Studies on LBW offspring specifically indicate dysfunction at several aspects of the satiety pathway, as evidenced by reduced satiety and cellular signaling responses to leptin. Recent studies have demonstrated an upregulation of the hypothalamic nutrient sensor nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin 1 (SIRT1), a factor that epigenetically regulates gene transcription of factors critical to neural development. Importantly, neuronal stem cells from rodent SGA fetuses and newborns demonstrate reduced growth and impaired differentiation to neurons and glial cells. Thus impaired neuronal development, and ultimately reduced satiety pathways, may be a consequence of a reduction in neural stem cell growth potential and reduced leptin-mediated neurotrophic stimulation during periods of axonal development.

Leptin secreted by adipose tissue and insulin secreted by the pancreas suppress neuropeptide Y (NPY) and increase proopiomelanocortin (POMC). 3V, third ventricle; AgRP, agouti gene–related protein; ARC, arcuate nucleus; LHA, lateral hypothalamic area; NTS, nucleus of the solitary tract; PVN, paraventricular nucleus.

In addition to appetite/satiety dysfunction, mechanisms that regulate adipose tissue development and function (lipogenesis) may be a key factor in the development of programmed obesity. Increase in adipose tissue mass or adipogenesis occurs primarily during prenatal and postnatal development, although some adipogenesis continues throughout adulthood. The process of adipogenesis requires highly organized and precisely controlled expression of a cascade of transcription factors within the preadipocyte ( Fig. 5-6 ), and this process is regulated by hormones, nutrients, and epigenetic factors. Of note, LBW offspring show a paradoxic increased expression of the principal adipogenic transcription factor, peroxisome proliferator–activated receptor gamma (PPARγ), and of hypertrophic adipocytes with increased propensity for fat storage, as evidenced by increased lipogenesis and de novo fatty acid synthesis. In accordance with this, LBW preadipocytes exhibit early differ­entiation and premature induction of adipogenic genes. Because the signaling pathways of adipogenesis and lipogenesis are upregulated prior to the development of obesity, they may be among the crucial contributory factors that predispose to programmed obesity. Furthermore, cellular studies indicate that in LBW infants, adipocytes at birth have fundamental traits identical to those seen with thiazolidine (PPAR agonist) treatment; that is, the adipocytes are more insulin sensitive and demonstrate increased glucose uptake and thereby facilitate increased lipid storage within the adipocytes. Thus early activation of PPAR or its downstream targets could promote the storage of lipids and thereby increase the risk of obesity. This concept reverberates with studies on maternal exposure to PPAR agonists, which induces fetal mesenchymal stem cells along the adipocyte lineage and causes a reduction in the osteogenic potential in these cells, resulting in greater fat mass in adult offspring. The role of stem cell precursor programming in metabolic disease pathways in response to maternal nutrient supply is an intriguing area for understanding developmental plasticity and potential preventive therapeutic strategies. Also, the potential transdifferentiation of white adipose tissue toward a brown-fat phenotype, which can expend energy via thermogenesis, offers an alternative preventive strategy for programmed obesity.

Transcriptional regulation of adipogenesis. C/EBP, CCAAT/enhancer binding protein; PPAR: peroxisome proliferator–activated receptor; RXR, retinoic X receptor; SREBP, sterol regulatory element–binding protein.

Offspring born to obese rat dams fed a high-fat diet also demonstrate increased food intake, adiposity, and circulating leptin levels and impaired glucose homeostasis dependent upon the period of exposure. In addition, these offspring have an activated adipose tissue renin-angiotensin system that partly contributes to their hypertensive phenotype. The underlying phenotype appears to be similar to that of LBW infants, with altered appetite regulation, enhanced adipogenesis, and reduced energy expenditure. Nonetheless, salient mechanistic differences exist, such as increased proliferation of appetite-stimulating or orexigenic neurons in the fetus, the inability of elevated leptin to downregulate NPY, and decreased PPARγ corepressors.

Hepatic Programming

In conjunction with the increased incidence of childhood and adolescent obesity, children and adolescents now have an increased risk of developing nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis, and type 2 diabetes. Type 2 diabetes has increased tenfold in some regions of the United States during the past decade, and the prevalence is particularly high in adolescent Native Americans, approaching rates of 6%. NAFLD, as determined by elevated serum aminotransferase, may occur in up to 10% of obese adolescents in the United States, although studies using ultrasonographic measures of fatty liver have estimated rates of up to 25% to 50% of obese adolescents. As a reflection of the severity of the metabolic syndrome, cases of cirrhosis associated with NAFLD in obese children have been described recently. Further evidence suggests that obesity can potentiate additional insults to the liver, such as with alcohol and hepatitis C infection.

Men and women with reduced abdominal circumference at birth, potentially reflecting reduced hepatic growth during fetal life, have elevated serum cholesterol and plasma fibrinogen. Similarly, poor weight gain in infancy is associated with altered adult liver function, reflected by elevated serum total and low-density lipoprotein (LDL) cholesterol and increased plasma fibrinogen concentrations. Although human studies have focused on the diagnosis and consequences of NAFLD in obese children and adolescents, animal studies (described below) indicate the early expression of fatty liver in fetuses exposed to maternal high-fat diets that were not LGA. Consequently, a heretofore undiagnosed increase in liver adiposity may exist among normal-weight offspring of mothers exposed to Western, high-fat diets.

Animal models of both maternal nutrient restriction and nutrient excess demonstrate the presence of NAFLD, alterations in liver structure, and changes in key metabolic transcription factors and enzymes involved in glucose-lipid homeostasis in offspring. Specifically, maternal protein restriction during a rat pregnancy shifts the enzyme setting of the liver in favor of glucose production, rather than glucose utilization, as evidenced by increased phosphoenolpyruvate carboxykinase and decreased glucokinase enzyme activities in offspring. Furthermore, these key hepatic enzymes of glucose homeostasis retain the ability to respond to the challenge of a high-fat, high-calorie diet but with an altered “set point” of regulation. Moreover, because these enzymes are predominantly located in different metabolic zones of the liver (glucokinase in the perivenous and phosphoenolpyruvate carboxykinase in the periportal zone), these altered activities have been attributed to clonal expansion of the periportal and contraction of the perivenous cell populations.

Five potential mechanisms lead to abnormal hepatic lipid metabolism and NAFLD ( Fig. 5-7 ). On a molecular level, PPAR transcription factors are implicated in regulating lipid metabolism. PPARα in particular is predominantly expressed in the liver and regulates genes involved in fatty acid oxidation. Although PPARγ is expressed at very low levels in the liver, PPARγ agonists have been shown to ameliorate NAFLD in a rat model. In addition, PPARα and PPARγ modulate the inflammatory response, and PPAR activators have been shown to exert antiinflammatory activities in various cell types by inhibiting the expression of acute-phase proteins, such as C-reactive protein (CRP). CRP is produced by hepatocytes in response to tissue injury, infection, and inflammation and is moderately elevated in obesity, metabolic syndrome, diabetes, and NAFLD. Rat studies have demonstrated NAFLD and elevated hepatic CRP levels in LBW adult offspring associated with reduced expression of hepatic PPARγ and PPARα. PPAR transcription factors and their coregulator peroxisome proliferator–activated receptor gamma coactivator (PGC-1α) are in turn regulated by SIRT1, which is a nutrient sensor that has epigenetic effects. Consistent with reduced PPARα, LBW offspring have reduced hepatic SIRT1 activity and PGC-1α expression, which likely promotes hepatic lipogenesis and suppresses hepatic lipolysis. Similar changes of reduced hepatic SIRT1 activity and PGC-1α expression are observed in offspring from maternal high-fat diet and obese pregnancies.

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