Perinatal Origins of Obesity

Chapter 50

Obesity/Perinatal Origins of Obesity T’ng Chang Kwok*, Shalini Ojha†,‡ and Michael E. Symonds* *Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, United Kingdom, † Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Derby, United Kingdom, ‡ Neonatal Intensive Care Unit, Derby Teaching Hospitals NHS Foundation Trust, Derby, United Kingdom

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There is mounting evidence to support the “Developmental Origins of Health and Disease” concept, which depicts the perinatal origins of obesity. Dysregulation of the hypothalamus-adipose axis, through changes in the concentrations of circulating factors and potential epigenetic modifications, is considered to cause perinatal programming of obesity in later life in response to perinatal insults such as maternal malnutrition and rapid weight gain postnatally. Obesity in early life is not only associated with long-term obesity in adulthood. It is also associated with metabolic, cardiorespiratory, orthopedic, and psychological disorders in childhood. A better measure of obesity in early life would be one that discriminates between fat and fat-free mass in order to provide a better understanding of the perinatal programming of obesity and aid in determining the optimum gain in growth parameters. Future studies should identify early life modifiable determinants of obesity that could be targeted to prevent long-term obesity and its associated disorders.

50.1 BACKGROUND Obesity is a global phenomenon and poses a significant public health concern. Worldwide prevalence of obesity has tripled over the last 40 years.1 In 2016, the World Health Organization (WHO) estimated that 13% of adults (11% of men and 15% of women) or 650 million adults are obese.1 Obesity is no longer just a problem in high-income countries or the developed world; the rate of obesity is increasing in low- and middle-income countries as well, particularly in the urban setting. Globally, there are more adults who are overweight or obese than underweight. This is a major concern, as more deaths worldwide are linked to obesity than factors associated with being underweight. Obesity is one of the most important risk factors for ischemic heart disease and premature death in adults.2 The situation is similar in children. The prevalence of obesity in children less than 5 years of age has increased by more than a quarter in 25 years to 41 million children in 2016.3 Interestingly, the rate of increase in the prevalence of obesity in these children is 30% faster in developing than in developed countries.1 In 2016, nearly half of children under 5 years of age living in Asia were overweight or obese.1 The number of overweight children under 5 years of age has also increased by nearly 50% in Africa over the last 15 years.1 If the current trend continues, it is estimated that the prevalence of obesity in children less than 5 years of age will reach 70 million by 2025.3 This is alarming, as epidemiological studies have found that infant and childhood obesity persist to adulthood, alongside the associated health risks.4 In view of the significant public health impact of obesity, various international and government agencies have attempted to put in place a wide range of initiatives aimed at reducing and preventing obesity in children and adults with limited success. However, current evidence suggests that these efforts should also be started very early on in life, even before conception. The concept of the “Developmental Origins of Health and Disease,” or DOHAD, suggests a perinatal origin of obesity.5 Changes during the critical period of development very early on in life may permanently alter the physiological function and metabolism, leading to long-term diseases.4,6 This chapter aims to explore how perinatal changes lead to the development of obesity, including its pathophysiology and long-term manifestations. A better appreciation of the perinatal origins of obesity will improve efforts aimed to prevent obesity by targeting the critical period of early life development. Maternal-Fetal and Neonatal Endocrinology. https://doi.org/10.1016/B978-0-12-814823-5.00051-9 Copyright © 2020 Elsevier Inc. All rights reserved.

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50.2

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WHAT IS OBESITY?

Obesity occurs when there is an imbalance between the intake and expenditure of energy. This leads to an abnormal accumulation of fat that has important health consequences such as obesity, diabetes, and cardiovascular disorders. In adults, body mass index (BMI) is a useful epidemiological tool in measuring obesity at a population level. BMI is derived from an individual’s weight in kilograms divided by the square value of the height in meters. An adult is defined as obese if the BMI is above 30 kg/m2.1 As BMI varies with age, the definition of obesity in children is more difficult. The WHO defined obesity in children between 5 and 19 years of age as BMI greater than two standard deviations above the WHO Growth Reference median.3 In children less than 5 years of age, obesity is defined as weight for height greater than three standard deviations above the WHO Child Growth Standard medians.3 However, it is important to note that BMI is only a rough guide and not a true measure of the amount of fat in an individual. Obesity is even more difficult and complex to define in the context of the fetus and neonate.

50.2.1

Fetal Macrosomia

Fetal macrosomia is a term often used in obstetrics as a description of excessive fetal growth and refers to an infant who was born large for gestational age. Fetal macrosomia is not only associated with a higher risk of birth complications and metabolic disturbances during the neonatal period; an infant who is macrosomic is also at a greater risk of becoming obese in adulthood, alongside its associated cardiovascular and metabolic diseases.7 There is a lack of consensus in defining fetal macrosomia. It is commonly defined either as an absolute birthweight value above 4000, 4500, or 5000 g, or as birthweight above the 90th, 95th, or 97th percentile for the infant’s gestational age.8 However, these definitions do not provide information on fetal obesity, as they do not discriminate between normal and abnormal body compositions. Besides the inconsistency in the definition of fetal macrosomia, the measurement of fetal macrosomia antenatally, using either clinical findings or diagnostic imaging, is also fraught with difficulty.

50.2.1.1 Clinical Findings Prediction of fetal macrosomia based on clinical findings is poor, with detection rates between 40% and 50%.9 Measurement of symphysis-fundal height was found to predict fetal macrosomia better than just abdominal palpation. Plotting the measured symphysis-fundal height on a customized growth chart improved the detection of fetal macrosomia antenatally. A Cochrane review, however, found insufficient evidence to evaluate the use of symphysis-fundal height measurement in antenatal care,10 but it may not be prudent to abandon its use unless larger clinical studies find it ineffective.

50.2.1.2 Ultrasonography Ultrasonography is a commonly used imaging modality during pregnancy to monitor fetal growth. However, the image quality is limited by multiple factors, including the sonographer experience and maternal adiposity. There are various sonographic formulations to estimate fetal weight, such as the Hadlock formula, and recent updates have taken into account measures of fetal adiposity. These include measures of the fetal upper arm or thigh subcutaneous tissue thickness, fetal cheek-to-cheek diameter, and fetal anterior abdominal wall width.8 There is a large deviation among the sonographic formulations, as they are derived from a heterogeneous group and are not meant to estimate fetal weight on the upper limit of the scale. Hence there is an ongoing debate as to which is best for predicting fetal macrosomia.8 A review of 20 studies11 found the posttest probability for identifying fetal macrosomia sonographically to differ greatly, from 15% to 79%. The variation in accuracy was found to not be affected by the formulation used, the interval between ultrasonography and delivery of the fetus, or the experience of the sonographer. The performance of 36 commonly used sonographic formulations in estimating the fetal weight to identify fetal macrosomia was also recently reviewed.12 It concluded that there was no sonographic formulation that reached an appropriate detection rate to be recommended in routine clinical practice. Some studies even suggest that these sonographic formulations are no better at predicting fetal macrosomia than clinical predictors.8 Apart from identifying fetal macrosomia, sonography could be used to perform Doppler studies on the umbilical cord and ductus venosus blood flow. These may provide an early indicator of the physiological changes leading to obesity. Ductus venosus shunts well-oxygenated placental blood from the liver to the brain and heart. A study of a cohort of 381 women with low-risk pregnancy in Southampton13 found that women with lower adiposity and healthier diet had lower ductus venosus blood shunting and higher hepatic blood flow on Doppler sonography. This is in contrast to cases of

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placental insufficiency, where there is reduced hepatic and increased ductus venosus blood shunting, which is characteristic of the brain-sparing response to fetal hypoxemia.

50.2.1.3 Magnetic Resonance Imaging Magnetic resonance imaging (MRI) has also been used to identify fetal macrosomia. A recent systematic review found MRI to be superior to 2D or 3D ultrasonography to detect fetal macrosomia.14 Meta-analysis of the three MRI studies of 117 women found a sensitivity of 0.82 (95% confidence interval [CI] of 0.60–0.95) and specificity of 0.98 (95% CI of 0.92– 1.00) in using MRI to predict birthweight above the 90th percentile.14 However, since the finding is based on a small sample size and measurement, a further diagnostic accuracy study is needed.

50.2.2

Neonatal Obesity

The measurement of obesity in neonates is also fraught with difficulties due to the lack of consensus on its definition and the ideal way of measuring obesity.

50.2.2.1 Body Mass Index BMI can be measured in the newborn and expressed as a Z score or standard deviation score to take into account gestational age and sex. Although BMI provides information on the nutritional status in adult whereby adults with a high BMI are associated with metabolic syndrome and cardiovascular disorder, this relationship in the newborn infant is unclear. Moreover, BMI may not provide a true reflection of body composition, as it does not distinguish between fat and fat-free mass. For example, an infant with low BMI may have higher relative body fat mass with a lower fraction of fat-free mass than another infant with a higher BMI. This is crucial, as it is the abnormal accumulation of body fat in childhood that leads to long-term obesity and health consequences.15

50.2.2.2 Body Composition Body composition measurement provides a better reflection of obesity and its associated long-term health outcomes. However, the lack of reference data makes it hard to interpret individual measurements, so they are not widely used in clinical practice.16 Furthermore, there are various techniques incorporating a variety of theoretical assumptions in estimating the fat and fat-free mass with variable agreement.16 Skinfold thickness is a quick, commonly used method of measuring body composition with low intra- and interobserver variability. Although there are formulas to predict the percentage of total body fat using skinfold thickness, it is a measure of regional adiposity rather than total body fat. Its accuracy and precision are also noted to be reduced in obese children.17 The isotope (deuterium) dilution is another method of measuring body composition. Total body water is the main component in fat-free mass. Hence, if the ratio of total body water to fat-free mass is known, fat mass can be estimated. A small amount of water labeled with a nonradioactive trace of deuterium is administered to the infant. Isotope-ratio mass spectrometry is then used to analyze subsequent urine samples to estimate the total body water.17 The ratio of the total body water to the fat-free mass is fairly constant in healthy infants. However, in diseased states whereby the hydration status of the infants is affected, there may be high variability in the ratio. Besides, this method cannot be carried out easily in clinical practice and is impractical in newborn infants. Bioelectric impedance analysis (BIA) measures the impedance of body to small electric current. It relies on the fact that the body contains intracellular and extracellular fluid that conducts electric current. By knowing the impedance value of human muscle tissue, body composition can be obtained by estimating the fat-free mass.17 Hence BIA is similarly affected by clinical hydration status and environmental temperature. BIA is not successfully used in infants, as anthropometry alone was found to be a better predictor of fat-free mass than BIA.18 Dual energy X-ray absorptiometry was initially developed to assess bone mineral mass by measuring the differential absorption of two different energy X-rays. Using specific algorithms, relative fat and fat-free mass can be obtained using a similar method. Although useful in identifying the direction of change of fat and fat-free mass, there is bias in quantifying fat and fat-free mass accurately.17 Densitometry relies on the concept that fat and fat-free mass have different specific densities. Hence body composition can be obtained by measuring body density. A commonly used technique is air displacement plethysmography, which is useful in monitoring changes in body composition over time. However, it is not accurate in cases whereby fat-free mass may be abnormal. For example, this may be due to fluid retention, which lowers the density of fat-free mass. It also conceals the regional variability of fat mass, which may have important health consequences.17

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MRI was recently used to estimate the volume of adipose tissue in neonates by analyzing the absorption and emission of electromagnetic energy.19 However, it is difficult to compare the MRI findings with another method of body composition measurement. This is because assumptions need to be made on the fat content and its density in adipose tissue to convert adipose tissue volume to fat mass.17 The cost and availability of MRI may also limit its widespread use.

50.3

DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE

The idea of perinatal origins of obesity and the “Developmental Origins of Health and Disease” concept stem from the perinatal programming hypothesis, which is often called the Barker hypothesis.20 This was initially hypothesized from findings obtained from numerous large epidemiological studies. These studies found that the intrauterine and early postnatal periods are critical for the development of long-term health diseases in adulthood, including obesity. Changes in the environment during this critical period, especially with regard to the metabolic nutritional state, result in the fetus or infant making predictive adaptations to the metabolic physiology, known as the thrifty phenotype.21 These adaptations were meant to improve the chances of survival and success in the long term if the initial changes were to continue into adulthood. However, these adaptations may have a permanent negative impact on organ and tissue structure as well as function. The epigenetic profile of the fetus and infant may be altered as well, leading to changes in gene expression. As a result, the physiological function of the body is permanently altered, potentially leading to energy balance dysfunction and long-term diseases such as obesity, diabetes, and cardiovascular disorder in adulthood. This situation is especially worsened if there is a mismatch between the initial perinatal environment and the postnatal reality.22,23

50.3.1

From Epidemiological Studies to DOHAD

The trio of papers published by Barker et al.24–26 in the Lancet in the late 1980s and early 1990s were among the most influential papers that sparked the Barker or perinatal programming hypothesis. The first paper24 found a significant geographical correlation between ischemic heart disease in 1968–1978 with infant mortality rates in 1921–1925 across the local authorities in England and Wales. It was proposed that the relationship reflected the variation in early life nutrition being expressed pathologically on exposure to later dietary influences. The second paper25 corroborated the findings of the earlier paper and investigated the individual correlation of birthweight and ischemic heart disease. Retrospective analysis of 5654 adult males born between 1911 and 1930 in Hertfordshire was carried out with good perinatal and death from ischemic heart disease records. Men with the lowest birthweight had a higher death rate from ischemic heart disease. Hence the paper concluded that the risk of ischemic heart disease is determined by the initial environment that led to poor fetal and infant growth, followed by an adult environment that determines high risk for ischemic heart disease. The third paper26 found evidence for changes in placental and fetal hormones, such as growth hormone and insulin-like growth factor being associated with fetal undernutrition at different gestation. These adaptations permanently alter the structure, function, and metabolism of the body, leading to metabolic and cardiovascular abnormality in adulthood. Similar studies, such as the Dutch famine cohort study during the end of World War II27 and Helsinki birth cohort study from 1934 to 1944,28 also demonstrated similar findings. Early life growth and nutrition affect the development of chronic diseases in adulthood such as obesity, cardiovascular disorders, and metabolic syndrome. The effect of nutrition on longterm outcome also differs, depending on which part of fetal development malnutrition occurs. This will be discussed in more detail as follows.

50.3.2

“U”-Shaped Relationship

Epidemiological studies also found that perinatal programming operates in a nonlinear “U”-shaped curve manner, whereby overnutrition or high birthweight also leads to adult metabolic syndrome alongside undernutrition or low birthweight.22 Infants who are large or those who are small for gestational age at birth are both noted to share some similarities, suggesting a potential common mechanism for perinatal programming in these two opposite environmental insults. The size discrepancies seen in these infants are usually selective,29 whereby head circumference is usually maintained with a disproportionate abdominal circumference, which is increased in large for gestational age infants and reduced in small for gestational age infants. This is postulated to safeguarding the brain at the expense of subcutaneous fat, liver, and spleen. In addition, both large and small for gestational age infants developed hypoglycemia and poor carbohydrate tolerance in the newborn period.29 Large for gestational age infants are exposed to excess nutrition in utero, leading to fetal

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hyperglycemia. This stimulates the fetal pancreas to secrete insulin, causing fetal hyperinsulinemia. As insulin is a growth promoting factor, these infants are born large for gestational age. As the hyperinsulinemia persists postnatally with cessation of the supply of excess nutrition received in utero, they develop hypoglycemia and poor carbohydrate tolerance at birth. Conversely, small for gestational age infants are exposed to undernutrition in utero, leading to fetal hypoglycemia and hypoinsulinemia. This persists postnatally leading to infants being born small, as well as developing hypoglycemia and poor carbohydrate tolerance at birth.

50.4 HYPOTHALAMUS-ADIPOSE AXIS The hypothalamus-adipose axis (Fig. 50.1) plays a vital role in maintaining energy homeostasis and controls food intake as well as energy expenditure and storage.30 The axis is a key target of developmental programming in obesity caused by prenatal and perinatal changes.31 Hence it is crucial to have a good appreciation of the hypothalamus-adipose axis and how it is regulated. This will aid in the understanding of the pathophysiology of perinatal programming of obesity.

50.4.1

Hypothalamus

The hypothalamus develops from the ventral region of the lateral wall of diencephalon known as the alar plate. A key marker of hypothalamic tissue development is the induction of the Nk2 homeobox transcription factor Nkx2.1. The hypothalamus then differentiates into a number of nuclear areas under the influence of various transcription factors. This neurogenesis in hypothalamus occurs in a “lateral-medial” fashion whereby lateral nuclei developed first.32 As a result, the hypothalamus contains several nuclei that produce neuropeptides involved in key physiological functions, including appetite regulation.33 The perinatal period represents a critical period of organization and development of the appetite regulatory pathway in the hypothalamus.32 Various genetic and environmental factors during the perinatal period alter the structure and function of the appetite regulatory pathway, leading to obesity and chronic metabolic disease in adulthood.

FIG. 50.1 Schematic representation of the regulation of appetite and energy expenditure of the hypothalamus-adipose axis based on data from rodent studies. a-MSH, a-melanocyte stimulating hormone; 3 ventricle, third ventricle; AgRP, agouti-related peptide; Arc, arcuate nucleus; DMN, dorsomedial nucleus; GC, glucocorticoids; GHS-R, growth hormone secretagogue receptor; GR, glucocorticoid receptor; InsR, insulin receptor; LHN, lateral hypothalamic nucleus; NPY, neuropeptide Y; Ob-R, leptin receptor; POMC, proopiomelanocortin; PVN, paraventricular nucleus; VMN, ventromedial nucleus. Modified from Wattez JS, Delahaye F, Lukaszewski MA, Risold PY, Eberle D, Vieau D, et al. Perinatal nutrition programs the hypothalamic melanocortin system in off spring. Horm Metab Res 2013;45(13):980–90; Ramamoorthy TG, Begum G, Harno E, White A. Developmental programming of hypothalamic neuronal circuits: impact on energy balance control. Front Neurosci 2015;9:16.

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50.4.1.1 Appetite Regulatory Pathway The arcuate nucleus in the hypothalamus plays a central role in food intake and energy homeostasis. It is located mediobasally in the hypothalamus next to the third ventricle and medial eminence. The arcuate nucleus integrates peripheral information from hormones such as insulin and ghrelin, adipocytokines such as leptin and adiponectin, as well as nutrients such as glucose and free fatty acid.30,31 This is possible, as it has a leaky blood brain barrier allowing circulatory factors easy access to the neurons, which also receive peripheral input regarding nutritional status from the vagal nerve.34 From the information received, the arcuate nucleus then modulates two neuronal populations, which are characterized by their expression of specific neuropeptides that regulate appetite. These are the anorexigenic neuropeptides, pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART), as well as the orexigenic neuropeptides, neuropeptide Y (NPY), agouti-related peptide (AgRP), and g-aminobutyric acid (GABA).31,35,36 These two neuronal populations counterregulate each other to modify appetite and energy expenditure, which ultimately regulate body weight. The arcuate nucleus then drives second order neurons in other hypothalamic nuclei such as the ventromedial nucleus (VMN), dorsomedial nucleus (DMN), paraventricular nucleus (PVN), which is also known as the satiety center, and lateral hypothalamic nucleus (LHN), which is also known as the hunger center. Several of the hypothalamic nuclei, especially PVN, regulate appetite and energy expenditure, such as lipolysis and thermogenesis in adipose tissue by the nucleus of solitary tract and sympathetic autonomic nervous system33 (Fig. 50.1).

50.4.1.2 The Action of Neuropeptides Expressed by Neurons in the Arcuate Nucleus POMC is broken down into various peptides, including adrenocorticotropic hormone (ACTH), b-endorphin, and a-melanocyte stimulating hormone (a-MSH). a-MSH is the most widely studied derivative of POMC. It has an agonist action at melanocortin-3 (MC3R) and melanocortin-4 receptors (MC4R) expressed on second-order neurons in other hypothalamic nuclei such as the lateral hypothalamic and paraventricular nuclei. This leads to a decrease in the expression of orexigenic peptides such as orexin and melanin concentrating hormone (MCH) in the LHN, but an increase in the expression of anorexigenic peptides such as corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) in the PVN.31 As a result, energy expenditure is increased while food intake is decreased. CART is a less studied anorexigenic neuropeptide due to the limited understanding of its receptor. It was found to have a similar effect as POMC and is thought to be secreted from the same arcuate neurons as those which secrete POMC,36 but is more widely expressed throughout the brain and peripheral tissue.37 On the other hand, NPY binds selectively to Y1NPY (Y1R) and Y5NPY receptors (Y5R) expressed by second-order neurons located in other hypothalamic nuclei. NPY acts in the opposite way as a-MSH, resulting in decreased energy expenditure with increased food intake.31 On the other hand, AgRP is an endogenous antagonist for MC4R and regulates signaling events postreceptor.35 The neuronal projections of both POMC and AgRP areas also overlap indicating crossinteractions between the two neuronal populations. GABA is the least studied of the three orexigenic neuropeptides. It is found to have a similar role as NPY36; it regulates the initial phase of appetite and can be a substitute for NPY. These neurons in the arcuate nucleus are one target of developmental programming of obesity especially induced by changes in maternal nutrition.35

50.4.2

Adipose Tissue

Adipose tissue develops from the accretion of fetal fat at 15 to 20 weeks of gestation, with an exponential increase in accumulation from 30 weeks of gestation.38 In the early phase, adipogenesis is associated with the deposition of subcutaneous fat, especially in the face.38,39 Visceral fat accumulation occurs later on in the middle of the second and third trimester. It accounts for 50% of maternal weight gain in the third trimester of pregnancy and 46% of the variation in birthweight.38 Adipocytes in the fetus are plastic and sensitive to various insults. Hence adipogenesis represents a window of vulnerability to insults during gestation and lactation.30

50.4.2.1 Role of Adipose Tissue Adipocytes are specialized cells with energy storage and endocrine roles. Excess energy is stored as triglycerides in lipid droplets in adipocytes during lipogenesis, whereby dietary fatty acids undergo simple esterification. When energy is required, lipolysis occurs, whereby stored triglycerides are hydrolyzed in a pathway driven by the sympathetic autonomic nervous system.31

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As an endocrine cell, adipocytes produce adipocytokines, hormones, and other appetite-regulating related peptides, which modulates energy homeostasis.40 Apart from regulating hypothalamic energy balance in an endocrine manner, adipocytes also act in an autocrine or paracrine manner to regulate lipid metabolism.30

50.4.2.2 Types of Adipose Tissue Adipose tissue is composed mostly of mature adipocytes and stromal vascular tissue consisting of preadipocytes, fibroblasts, and endothelial as well as immune cells. There are different types of adipose tissue, such as white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue.30 WAT functions as long-term energy storage. It is derived from preadipocytes recruited from precursor cells with vascular origins from adipogenesis.41 This is driven by transcription factors like peroxisome proliferator activated receptor alpha (PPARa) and lipid metabolizing enzymes such as fatty acid synthase.30 Adipocytes in WAT are characterized by a single unilocular lipid droplet that stores excess energy as triglycerides.30 BAT plays an important role in energy expenditure through thermogenesis, producing a large amount of heat when maximally stimulated.42,43 This occurs by the activation of uncoupling protein 1 (UCP1) found within the inner mitochondrial membrane.44 BAT first appears in the fetus during mid-gestation and gradually declines throughout childhood and adulthood. It has a close developmental relationship with myocytes, where it is derived from the Myf5-positive myoblastic lineage.45 BAT is characterized by multilocular smaller lipid droplets with a large number of mitochondria and expression of UCP1.44 BAT is found in small quantities, accounting for up to 4% of the total body weight even at its prominent stage in newborns.43 Despite so, BAT has great potential in having a significant impact on energy balance. Beige adipose tissue is found within some WAT depots and shares many morphological and functional features of BAT. However, the amount of UCP1 is only 10% of that of BAT.46 Beige adipose tissue also has its own unique genetic markers and is thought to share the same origins as WAT, deriving from precursors cells with vascular origins.30 Hence the presence of beige adipose tissue may suggest a source of adipose tissue found sparsely within WAT, which is potentially converted or recruited into BAT.47

50.5 THE MECHANISM LEADING TO PERINATAL ORIGINS OF OBESITY The programming of obesity is dependent on two closely interacting factors. These are the complex genetic factors that predispose individuals to energy balance dysfunction, as well as the environmental insults during the critical period of development. These may then alter the energy homeostasis pathway with permanent consequences such as obesity.31,36 The mechanism by which an environmental insult during early development, especially during the perinatal period, affects the programming of obesity remains unclear. One plausible explanation may be the suboptimal level of circulating factors due to the environmental insults such as malnutrition (Fig. 50.2). This causes permanent changes to the structure and function of organs, especially the hypothalamus-adipose axis, resulting in the perinatal programming of obesity. Another potential mechanism for developmental programming of obesity is the regulation of gene expression in a spatial and temporal manner due to epigenetic modifications (Fig. 50.2). There is increasing interest in how epigenetic dysregulation of energy homeostasis genes induced by early life environmental insults may account for the persistent changes in metabolic phenotype.36,48

50.5.1

Circulating Factors

Metabolomics is a study of the metabolic response to pathological environmental insults and genetic modifications by making quantitative measurements over time. It has generated new hypotheses with regards to mechanisms surrounding the perinatal origins of obesity by describing the biochemical and molecular profile of obesity. The crucial circulating biochemical factors in obesity are hormones such as insulin and ghrelin, as well as adipocytokines such as leptin. The roles of these circulating factors have been previously described in Chapter 39, “Origins of Adipose Tissue and Adipose Regulating Hormones.” Nutrients such as glucose also interact with the arcuate nucleus in the hypothalamus in regulating energy homeostasis. Glucose is taken up by the POMC/CART neurons by glucose transporter GLUT 2. Glucose is then phosphorylated and metabolized to generate ATP, which binds to and block the KATP channel. As a result, the POMC neuron is depolarized, activating the anorexigenic secondary order neurons.35

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FIG. 50.2 Common perinatal insults resulting in the perinatal programming of obesity and its associated consequences.

50.5.2

Epigenetics

Epigenetics is the study of stable and inheritable changes in gene function without changing the underlying deoxyribonucleic acid (DNA) sequence. Transient environmental insults during prenatal and early postnatal life, especially changes in maternal or perinatal nutrition, may permanently imprint the offspring’s genome and alter the transcription of genes crucial in energy homeostasis. This leads to long-term energy homeostasis dysfunction and sensitizes the offspring to obesity and metabolic syndrome in adulthood.31 The phenotype of some epigenetic modifications may not be present until later in life, especially in genes modulating responses to later environmental changes.49

50.5.2.1 Epigenetic Mechanism There are three postulated mechanisms of epigenetic modification.36 They are the methylation of DNA, posttranslational histone protein modification, and micro RNA (miRNA) mediated gene regulation. DNA methylation is the most common and well-understood mechanism for producing highly stable epigenetic modification. It plays an important role in altering gene transcription by methylation of promoter genes, parental imprinting, and X chromosome inactivation.50 DNA methylation involves a covalent modification by adding a methyl group. The methyl group is commonly added to the C5 position of cytosine residue that is adjacent to the guanine residue. This pair of dinucleotides is called a CpG dinucleotide. DNA methyltransferase catalyzes this process and requires a cofactor and methyl donor in the form of S-adenosylmethionine.36 The methyl group of the S-adenosylmethionine is usually obtained from dietary nutrients such as folic acid. Hence dietary modification may alter the process of DNA methylation. DNA methylation subsequently affects gene expression by either preventing transcription factors from binding to recognized sites on the DNA, or stimulates binding of methyl-CpG-binding protein (MBP), which recognizes methylated DNA and recruits transcriptional co-repressor complexes, leading to gene silencing. Hence CpG methylation in the promoter region is generally associated with gene silencing.51 Histone packages DNA into nuclear chromatin. Numerous covalent modifications can occur on the N-terminal of the core histone, resulting in alterations of the chromatin organization and gene expression. Hence the epigenetic modification of histone

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can have a profound effect on gene transcription.36 Examples of posttranslational histone modifications include acetylation, methylation, phosphorylation, and ubiquitination of histone.52 Acetylation occurs on the lysine residue of histone, which is generally associated with initiation or elongation of gene transcription. Methylation can occur at either the lysine or arginine residues of histone, which is associated with either transcription activation or silencing, depending on the residue modified.52 Hence a combination of different epigenetic modifications of histone can regulate the activation and silencing of genes. MicroRNA (miRNA) is a new class of regulatory molecules that control gene expression at the posttranscriptional level. It exerts an epigenetic effect by being part of a complex network of reciprocal interconnection and regulatory loops, as well as regulating the DNA methylation and histone protein modification. In turn, expression of miRNA is regulated by the DNA methylation and histone protein modification.53 These epigenetic modifications to anorexigenic and orexigenic genes in the hypothalamus can alter the appetite regulatory pathway and body weight set point. This leads to the perinatal programming of obesity and metabolic disorder in later life.36

50.5.2.2 Examples of Epigenetic Modification A human twin pair study54 found DNA methylation and histone modification to diverge strongly in twin pairs with marked differences in life history and environmental insults. Hypothalamic POMC gene is a likely target for epigenetic modification as a result of perinatal programming, as it is regulated by promoter region methylation.31 Changes in the perinatal nutrition may cause an epigenetic modification in the key regulatory elements of the POMC promoter region. This subsequently affects the appetite regulatory pathway in the hypothalamus, resulting in obesity. Maternal undernutrition during periconception in sheep is associated with hypomethylation of fetal hypothalamic POMC gene.48 Animal studies in rodents demonstrated that neonatal malnutrition is associated with the hypermethylation of the CpG sites required for leptin and insulin expression of POMC in the hypothalamus.55 Hence this leads to leptin and insulin resistance, as well as obesity. Hypomethylation of specific CpG sites and increased acetylation of histones in the promoter region of NPY are observed with feeding newborn rodents a milk high in carbohydrate. This leads to an increased mRNA expression of NPY and subsequently obesity in adulthood.56 Similarly, undernutrition in maternal sheep is associated with hypomethylation and histone protein modification of the GR promoter region. This leads to an increased GR mRNA expression in the fetal hypothalamus that regulates energy homeostasis,57 but long-term effects have not been investigated. Imprinted genes are another target for epigenetic modification and include the insulin like growth factor 2 (IGF2) gene, which controls growth and metabolism in the fetus and early life.49 Parental imprinting of the IGF2 gene has a labile methylation pattern, which is highly dependent on the nutritional status in early life.58 The Dutch famine study59 found hypomethylation of the imprinted IGF2 gene 6 decades later in the offspring of mothers exposed to famine during periconception. This hypomethylation was not noted in unexposed same-sex siblings. Different epigenetic modifications on identical DNA sequences may permanently alter gene expression levels, leading to long-term hypothalamic dysfunction of energy homeostasis.35 It remains uncertain as to how epigenetic modification of specific genes associated with obesity is targeted by developmental programming. The timing and intensity of the environmental insult may play a significant role.36 It is also plausible that dietary factors can influence epigenetic modifications, especially methylation of genes involved in energy homeostasis and obesity. Micronutrients such as dietary folate, vitamin B6, and vitamin B12 are methyl group donors for the methylation of DNA and histone protein.60 Changes in nutrient and hormone levels may act as the mediator of downstream signals of environmental insults. Epigenetic modifications such as DNA methylation are potentially reversible. The metabolic changes can be reduced through nutritional intervention. For example, supplementation of folic acid, which is a methyl donor, during the critical period of perinatal development was found to prevent the increase in birthweight in subsequent generations caused by perinatal programming of obesity by epigenetic modification.61

50.5.2.3 Transgenerational Epigenetic Modification Animal studies found epigenetic modifications to extend beyond the first generation, even in the absence of exposure to the adverse environment previously experienced by the first-generation offspring.62 From an evolutionary point of view, the transgenerational transmission of epigenetic modifications allows future generations to better survive the potential adverse environment experienced by current generations. The mechanism behind this is unclear, but studies found epigenetic inheritance in both maternal and paternal linkages.49 The Dutch famine study found second-generation offspring to have increased neonatal adiposity and persistent changes in DNA methylation. Although many studies59 show transgenerational transmission of epigenetic modifications to the second generation, the transmission to the third and subsequent generation remains unclear.62

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50.5.2.4 Gender-Specific Effect of Perinatal Programming of Obesity There is emerging evidence demonstrating the gender-specific differences seen in the perinatal programming of obesity in offspring, which occurs in response to perinatal environmental insults, especially maternal malnutrition.30,35,36 This reflects the potential direct interaction between the biological mechanisms of perinatal programming of obesity with sex hormones in the developing fetus and newborn. The difference in sex hormones may modify the perinatal programming of the hypothalamus-adipose axis differently in response to environmental insults.63 For example, animal studies using rodents and sheep36,57 have found that male offspring that were exposed to maternal undernutrition during gestation were more likely to have lower insulin levels and were more sensitive to changes in insulin levels. They also had a higher fat mass than female offspring exposed to the similar environment. This may be because estrogen can regulate the changes in the insulin and leptin as a compensatory mechanism in response to maternal malnutrition. The brain in male offspring is considered to be more sensitive to leptin and insulin resistance associated with maternal malnutrition. The reduced central action of insulin in the male offspring may lower the expression of anorexigenic neuropeptides such as POMC, leading to increased appetite and obesity later on.36 The outcomes for male offspring are often noted to be worse than that in females in response to adverse perinatal environmental insults. Hence it is argued that the perinatal programming in male and female offspring differ with timing and outcome.63 Despite this, few studies currently pay close attention to the gender-specific effects in the perinatal programming mechanism.

50.6 ENVIRONMENTAL INSULTS RESULTING IN THE PERINATAL PROGRAMMING OF OBESITY Fetal and early postnatal environments have a significant impact on the risk of obesity and metabolic disorder in adulthood, as suggested by DOHAD. This section explores the perinatal environmental factors that lead to programming of obesity using human epidemiological studies (Fig. 50.2). Due to the limitations of human studies, it is difficult to investigate the precise biological mechanism of how these perinatal factors “program” obesity. These factors may exert their impact on the hypothalamus-adipose axis via the mechanisms described previously. Data from animal models are used to provide further evidence. Different animal models have their own limitations. Many animal studies on the perinatal programming of the hypothalamus-adipose axis use rodents that are an altricial species. The hypothalamus of the rodent is immature at birth and continues to develop by forming axonal projections and synapses to target sites during the first 2 weeks postnatally. Hence the hypothalamus is not fully formed at birth, making the hypothalamus-adipose axis plastic and sensitive to environmental insults postnatally.64 Different methods have been used to modify the environment during this critical period of hypothalamic development to aid in the understanding and characterizing of perinatal programming of obesity in humans. However, the length of gestation and hypothalamic development in altricial rodents are not comparable to that in humans. The timing of vulnerability of the environmental insults may differ markedly.64,65 Despite so, many studies show rodents displaying similar developmental programming to precocial species such as sheep and primates.31 In precocial species, the hypothalamic development and neuronal projection occur prenatally in the fetus stage.

50.6.1

Maternal Nutrition

Prenatal growth trajectory is sensitive to the direct and indirect effects of maternal nutrition.66 Numerous epidemiological and animal studies have found that maternal malnutrition, which encompasses both undernutrition as well as overnutrition during the perinatal period, creates an adverse environment for the fetus. As a result, persistent physiological changes occur in the fetal hypothalamic appetite regulatory pathway, causing perinatal programming of obesity and metabolic disorder in adulthood.48 This is especially the case when there is a difference between the prenatal and postnatal environments.67 Fetal programming induced by maternal malnutrition is thought to involve changes in the hypothalamic appetite regulatory pathway established during early development.

50.6.1.1 Maternal Undernutrition One of the first major epidemiological studies demonstrating a negative impact of maternal undernutrition during pregnancy and disease outcome in offspring is the Dutch famine study from 1944 to 1945.68 Maternal exposure to undernutrition at different periods of the gestation leads to a slightly different outcome in the offspring. Offspring whose mothers were exposed to famine early on in the gestation had normal birthweight but higher risk of obesity and metabolic disorders.69

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Offspring had low birthweight if their mothers were exposed to famine later on in gestation.68 This difference continues into late adulthood. Longitudinal analysis of the Dutch famine cohort found adults at 50 years of age whose mothers were exposed to undernutrition during early gestation had a higher risk of obesity, impaired glucose tolerance, and coronary artery disease, compared with those whose mothers were not exposed to malnutrition.70 The finding from human studies corroborated with those from animal studies. Maternal and perinatal undernutrition in rodents were associated with low birthweight and increased appetite postnatally, as well as obesity and insulin resistance in adults.71 The use of animal models to mimic maternal undernutrition during gestation has also shed some light on the biological mechanism of action. Maternal undernutrition in rodents was found to affect the structural organization of the hypothalamus in the fetus.31 Neuronal cell proliferation and axon projection in the hypothalamus were noted to be affected in maternal undernutrition. This alters the density of orexigenic and anorexigenic neurons such as neurons expressing NPY as well as POMC, respectively.72–74 As a result, regulation of energy homeostasis is impaired, causing obesity and metabolic disorders in adulthood. Maternal undernutrition also causes long-term programming of the appetite regulatory pathway in the arcuate nucleus of the hypothalamus, favoring the orexigenic pathway.31 Maternal undernutrition during gestation in rodents consistently demonstrated an increase in orexigenic neuropeptides such as NPY and AgRP, as well as a decrease in anorexigenic neuropeptides such as POMC.72,73 Similar findings were noted in baboons where offspring who were exposed to maternal undernutrition during gestation have a lower expression of POMC and a higher expression of NPY neuropeptides.75 In sheep,57 moderate maternal undernutrition was associated with an increased glucocorticoid receptor expression, which is sustained to adulthood. However, no changes in the POMC and NPY expression were noted at the fetal stage, but a decrease in the POMC expression was found in adulthood. Adipose tissue in infants of rodents and sheep exposed to maternal undernutrition during gestation was found to have an increased expression of proinflammatory genes and recruitment of macrophages within WAT.31 This leads to early insulin and/or leptin resistance, causing obesity and metabolic disorders in adulthood. Offspring of rodents exposed to maternal undernutrition were also found to have increased adipogenesis with an increase in adipocyte number and size. There was also reduced antilipogenic action by leptin noted.47 The noradrenergic supply to the WAT was also functionally impaired in rodents exposed to maternal undernutrition, potentially causing increased adipogenesis and/or decreased lipolysis.74

50.6.1.2 Maternal Overnutrition Overnutrition is becoming a major public health issue globally with the increasing prevalence of obesity, including obesity rates in pregnant women. Many human epidemiological studies have found that infants who are born to women who have raised BMI, especially in the first trimester, are at an increased risk of obesity and metabolic disorders in adulthood.66 Interestingly, offspring born to mothers who underwent bariatric surgery have a lower risk of obesity than offspring born before the surgery. However, human studies have their own limitations, as obesity is a lifelong condition that may precede pregnancy. Hence it is difficult to differentiate between gestational obesity and preconception obesity in women. Besides, it is difficult to eliminate all the confounding factors, as offspring may be exposed to the same adverse, obesity-predisposing environment postpartum that their mothers were exposed to during pregnancy. Animal models of maternal overnutrition, especially in rodents, where a high-fat low carbohydrate maternal diet is given during pregnancy and lactation, is associated with an increased risk of obesity and metabolic disorder in the offspring,31,36 without any change in birth weight. The neuronal axon projection of the anorexigenic and orexigenic neurons in the arcuate nucleus to the PVN is impaired in the offspring of maternal rodents fed the high-fat diet.76 An increase in the proliferation of the orexigenic neuropeptide expressing neurons and a reduction in that of the anorexigenic neuropeptides are noted in the offspring of rodents with maternal overnutrition.31 This subsequently alters the appetite regulatory pathway in the hypothalamus, leading to increased appetite and predisposing the offspring to obesity, which persists into adulthood. The impact of maternal overnutrition on gene expression of orexigenic and anorexigenic neuropeptides in the hypothalamus is diverse. Various studies have produced conflicting results,36 making it hard to interpret as compared with that of maternal undernutrition. Some of the changes seen in the neuropeptide levels in the offspring may be a compensatory mechanism for maternal overnutrition, which may change later on in life. Hence further research in this field is needed to provide further clarity on the impact of maternal overnutrition on the expression of these neuropeptides. Maternal overnutrition in rodents was also found to cause central leptin resistance in the offspring.31 This leads to an increase in the activity of the orexigenic pathway and a decrease in the activation of the sympathetic nervous system. As a result, the long-term body weight set point is altered, leading to obesity.

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Interestingly, obese mothers who lose weight during gestation can increase the risk of intrauterine growth (IUGR) restriction in their offspring, predisposing them to obesity in adulthood.77 The increased risk of IUGR may be due to a few reasons, including ketosis from the maternal mobilization of WAT; increased maternal cortisol level from weight lost, which inhibits fetal protein synthesis; or reduced fetal nutrient supply as a result of the increased utilization of nutrients by maternal tissue and the reduced uteroplacental blood flow.66

50.6.2

Maternal Glucose Control

Maternal diabetes is a common predisposing factor for having infants who are born large for gestational age and subsequently develop an increased risk of obesity and diabetes in adulthood. The direct relationship between birthweight and maternal blood glucose level is noted, even if the maternal glucose level is within the normal range.8 Interestingly, infants born to mothers after a maternal diagnosis of diabetes have a higher risk of raised BMI and diabetes in adulthood than their siblings born before the diagnosis.78 Maternal diabetes during gestation is associated with fetal hyperglycemia, as maternal glucose is transported by the placenta into the fetal circulation. This stimulates the b cell of the fetal pancreas, causing fetal hyperinsulinemia.79 As insulin is a growth promoting factor, the infant is often born large for gestational age.29 During the postpartum period, the infant is no longer exposed to the high glucose environment experienced prenatally due to maternal diabetes. Despite this, the hyperinsulinemia persists. As a result, the infant experiences hypoglycemia and subsequent poor carbohydrate tolerance.80,81 Animal models of maternal diabetes in rodents using an injection of pancreatic islet toxin streptozotocin early in the pregnancy also confirmed these findings and indicate some potential biological mechanisms.35 The offspring of diabetic maternal rodents have higher body weight and appetite with hyperglycemia.36 Structural changes in the hypothalamus are noted, with an altered density of AgRP and POMC expressing neurons in the hypothalamus as well as altered leptin sensitivity.82 This adverse programming of the appetite regulatory pathway in the hypothalamus predisposes the offspring to obesity and metabolic syndrome in adult life. It can potentially be prevented by normalizing maternal glucose during pregnancy.36

50.6.3

Multiple Births

Multiple births present a unique opportunity to investigate the impact of low birthweight on obesity and metabolic disorders. This is because the offspring share many similarities with the programmed offspring from maternal undernutrition, causing low birthweight.36 It may be because such offspring compete with each other for nutrition and have reduced placental size. Thus the offspring may develop compensatory mechanisms similar to that of the programmed offspring. This is seen in sheep, whereby such offspring can have a higher fat mass in adulthood with altered hypothalamic appetite regulatory pathway, as well as glucose regulation.83

50.6.4

Placental Insufficiency

The placenta plays a crucial role in fetal growth and development. It oversees the transfer of nutrients into the fetal circulation and acts as an endocrine structure, secreting hormones needed for fetal growth and development. The placenta senses changes in the maternal environment, especially maternal nutritional status, through pathways such as the mechanistic target of rapamycin (mTOR). The placenta responds to environmental challenges by altering its structure and function, resulting in changes in uteroplacental blood flow and hence fetal nutrient supply. It also secretes hormones and other signaling molecules in response to the environmental changes.84 This has a significant impact on fetal growth as well as body composition. Hence, when placental insufficiency occurs, the fetus is at risk of obesity and metabolic disorders in adulthood as a result of fetal programming. Placental insufficiency is not just purely due to impaired uteroplacental blood flow. It can also be caused by impaired surface area for the placenta to carry out its exchange function effectively, secondary to reduced intervillous space volume or poorly developed peripheral villi.84 Placental insufficiency predisposes the fetus to impaired transfer of nutrients, disrupting fetal growth and development during gestation, causing IUGR. The prevalence of IUGR is increasing in high-income countries and accounts for 11% of births in low to middle-income countries.66 In clinical practice, the term IUGR is often used interchangeably with small for gestational age, which is defined as having birthweight less than the 10th percentile for gestational age. However, it must be stressed that IUGR

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refers to the insufficient growth of the fetus. Hence the newer definition of IUGR requires at least two assessments of intrauterine fetal growth showing inappropriate growth of the fetus before the term IUGR could be used.85 IUGR is associated with many chronic diseases in adulthood, including obesity and metabolic syndrome.66 Animal models using bilateral artery ligation to mimic placental insufficiency and IUGR are often used to explore the biological fetal programming mechanism for nutritional regulation, as well as the development of long-term health outcomes. The induced placental insufficiency leads to a reduced supply of nutrients to the fetus, and hence fetal hypoglycemia and hypoinsulinemia occurs. This accounts for infants being small for gestational age, as insulin is a growth-promoting factor.36 The fetus then adapts to the adverse environment by altering the metabolic parameters or epigenetic modifications of stem cell population. These mal-adaptations are the basis of perinatal programming of obesity in placental insufficiency and IUGR.85 The fetal insulin hypothesis is proposed as a potential explanation for the long-term metabolic risks and obesity observed in infants with IUGR and low birthweight.85 As a compensatory mechanism for IUGR, there is an increase in expression of insulin-like growth factor 1 (IGF1) and its receptor, IGF1R, to enhance the transfer of nutrients such as glucose and amino acid into the fetus. After birth, a period of increased insulin sensitivity is seen with a reduction in the IGF1 and an increase in insulin-like growth factor binding protein 1 (IGFBP1) level. This increased insulin sensitivity is gradually lost and switches over to insulin resistance over the first 3 years of life at a rate relative to the postnatal weight gain. It has a potential adverse impact on the body composition and metabolic risk in later life.

50.6.5

Birthweight

Birthweight is often used to reflect the intrauterine environment and maternal nutritional status during gestation in human studies. The “thrifty” phenotype21 describes the fetal adaptation to the adverse intrauterine environment caused by maternal undernutrition and the subsequent low birthweight. The adaptation becomes maladaptive when there is increased nutrient availability postnatally, leading to obesity and metabolic disorders in adulthood. Conversely, emerging studies86 have found a positive relationship between high birthweight with high adult BMI, reflecting the impact of prenatal and maternal overnutrition on obesity and metabolic disorders in adulthood. Hence a U-shaped relationship between birthweight and adult obesity is seen in human epidemiological studies, with an increased risk in infants with both high and low birthweights. However, the postnatal environment, especially postnatal weight gain, is noted to have a more significant impact on the development of obesity in adulthood.85,86 Once postnatal weight gain is taken into account, some human epidemiological studies found that the birthweight is no longer a predictor of obesity in adulthood. It is also crucial to note that BMI is not an accurate surrogate marker of adiposity. The majority of the human epidemiological studies found high birthweight infants to have an increase in fat-free mass in adulthood without impact on the fat mass, as estimated by various means ranging from skinfold thickness to BIA and dual energy X-ray absorptiometry.4,86

50.6.6

Gestational Age

Recent advances in neonatal care have seen an increase in the number of premature infants surviving to adulthood. Hence there are a few studies looking at the long-term metabolic impact of prematurity. Many studies have found that infants who are born prematurely are at an increased risk of obesity, especially central obesity, which carries a poor metabolic risk profile.87 Reasons behind this finding are unclear at present, and more studies are needed to investigate the biological mechanism. One potential explanation is that many of these preterm infants experience some form of extrauterine growth restriction postnatally, despite potentially having normal fetal growth prior to birth. They are often very unwell, especially in the first few weeks of life, requiring high energy demand for growth and to overcome infection and respiratory distress. However, the amount of nutrient and energy that they received during this period of time often does not match their energy demand, causing extrauterine growth restriction.88 Hence they may undergo programming in response to this adverse environment. When premature infants recover from this initial period of high energy demand, they are often exposed to a high calorie and high protein milk to improve weight gain. This is because their poor weight gain is associated with poor neurodevelopment. Conversely, the metabolic programming in response to the initial extrauterine growth restriction may become maladaptive when exposed to the excessive weight gain as a result of the high calorie and high protein milk. Hence this may predispose preterm infants to obesity and metabolic disorders in adulthood.89

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Weight Gain in Early Infancy

Early infancy represents a period of many rapid changes with many of the organs and systems still in the developmentally plastic stage. Studies4 showed that the weight gain in infants in the first 6 months of life is mainly translated into a gain in the fat mass in relative terms. After that age, the gain in fat-free mass occurs more quickly. Hence excessive weight gain in early infancy, especially in the presence of an adverse prenatal environment or growth restriction, is found to be an important predictor of obesity and metabolic diseases in adulthood. This phenomenon is called catch-up growth. Human epidemiological studies found excessive catch-up growth to play a more significant role in predicting long-term obesity than birthweight alone.85,86 Rapid catch-up growth is thought to be caused by the increased appetite secondary to a sustained increase in the orexigenic drive, and adaptation or programming to ensure recovery of weight following the prenatal insult. This predisposes infants to obesity and metabolic diseases in later life. Epidemiological studies and randomized controlled trials conducted in developed countries found excessive weight gain in the early infancy period to play a significant role in predisposing infants to obesity in later life.4 A review of 10 epidemiological studies found that excessive weight gain in the first year of life is associated with obesity in later life based on BMI with a relative risk between 1.2 and 5.7.90 Further studies have found that rapid weight gain in early infancy is also associated with a poor body composition of a higher fat mass4 as well as truncal adiposity.86 This is crucial, as the BMI may not be a true reflection of adiposity and its metabolic consequences, as previously discussed. The crucial period of weight gain that has a significant impact on long-term obesity risk is unclear at present, with studies suggesting the first 3, 6, or 12 months of life.4 The evidence for the role of excessive weight gain in early infancy on obesity risk in developing countries, whereby growth stunting and undernutrition are common, is limited and conflicting. A review of five longitudinal studies from lowand middle-income countries (India, Brazil, Guatemala, Philippines, and South Africa) found that excessive weight gain in the first, second, and third year of life is associated with higher blood pressure in adulthood due to its contribution on the adult BMI rather than the weight gain itself.91 Hence further studies in developing countries are required, balancing the risk and benefit from excessive weight gain in early infancy. Preterm infants are another group of infants whereby excessive catch-up growth is noted to have a negative impact on long-term obesity and metabolic risks.4 However, poor postnatal growth is also a known independent risk factor for adverse neurodevelopmental outcomes.85 Hence further studies are needed to address the competing risks and benefits of excessive catch-up growth in preterm infants.

50.6.8

Nutrition in Early Infancy

Breastfeeding confers many benefits to both the mother and infant. There is mounting evidence from epidemiological studies that breastfeeding protects the offspring from obesity in later life. Infants who were exclusively breastfed, as well as those breastfed for longer (i.e., weaned later), have a lower BMI and fat mass in adulthood.92 The biological mechanism of how breastfeeding lowers the risk of adiposity in adulthood is unclear at present. Breastmilk contains numerous hormones and adipocytokines, such as insulin and leptin, that are crucial for the regulation of the infant’s appetite. The macronutrient and biologically active contents of breastmilk may also play a role, with a lower protein and higher docosahexaenoic acid (DHA) content in breastmilk.92 In animal models using rodents, breastfeeding was found to alter the expression of genes involved in energy homeostasis in the hypothalamus and WAT. As result, this alters the appetite-regulating pathway in the hypothalamus31 and increases the proliferation and differentiation of adipocytes.30 This leads to an increased appetite and perinatal programming of adiposity later on.

50.7

COMPLICATION OF OBESITY

Obesity is associated with complications affecting multiple systems and organs. This section aims to discuss the complications associated with fetal macrosomia and early childhood obesity.

50.7.1

Fetal Macrosomia

50.7.1.1 Maternal Risks Fetal macrosomia presents an increased maternal risk during labor and delivery. Fetal macrosomia is commonly associated with prolonged first and second stages of labor, with the risk increasing as birth weight increases.8 Arrest of fetal descent

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during the second stage of labor may also occur. This impacts the delivery mode of the fetus. Fetal macrosomia is found to increase the risk of Caesarean section as well as instrumental assisted vaginal delivery, especially in cases of primigravida. However, there is a wide variation in the reported overall rates of such delivery methods in fetal macrosomia.93 There is also a reported 1.5- to 2.5-fold increase in the risk of perineal tear associated with fetal macrosomia.93 Postpartum hemorrhage is also noted to be associated with fetal macrosomia. This may be due to a combination of factors, including prolonged labor, assisted vaginal delivery, uterine atony, and perineal tear.

50.7.1.2 Neonatal Risks Although the literature commonly demonstrates increased morbidity in infants with fetal macrosomia, the overall risk of complications is still low. Some of the commonly associated risks are shoulder dystocia, birth trauma, and metabolic disorders during the early postnatal period.8 Macrosomic infants commonly have a higher risk of developing shoulder dystocia at delivery, with variable rates of shoulder dystocia reported. Despite the association with fetal macrosomia, at least half of the infants who developed shoulder dystocia at the delivery are not macrosomic, having birthweights less than 4000 g.93 There is also an increased risk of birth trauma associated with fetal macrosomia. Similarly, the risk increases with increasing birthweight. Brachial plexus injury due to traumatic stretching is common in the macrosomic fetus, resulting in paresis of the upper extremity. This may be due to the exogenous traction applied or the endogenous pushing during delivery. A majority of the brachial plexus injuries self-resolve with minimal intervention. Skeletal injuries, especially clavicular fractures, are commonly seen in infants with fetal macrosomia, with an increased risk of up to five times93 in fetal macrosomia. Similarly, clavicular fractures are managed conservatively with a good long-term outcome. Neonatal hypoglycemia is common in infants with fetal macrosomia, especially if there is a background of maternal gestational diabetes. The transient fetal hyperinsulinemia associated with maternal gestational diabetes is thought to increase the risk of neonatal hypoglycemia.8,93 Fetal macrosomia is also found to be associated with neonatal hyperbilirubinemia during the early postnatal period.8 This may be partly due to the polycythemia, as well as the increased enterohepatic cycling of bilirubin seen in fetal macrosomia, especially in the presence of maternal gestational diabetes. Transient electrolyte disturbances are also noted in the early postnatal period in macrosomic infants. The hypomagnesemia and hypocalcemia seen are often asymptomatic and do not require treatment.8

50.7.2

Early Childhood Obesity

50.7.2.1 Obesity in Adulthood Various studies carried out in different population settings have found that infant and early childhood obesity have moderate to strong correlation with obesity in adulthood.94 This is especially true if the child has higher BMI or has parents who are obese.94 By 5 years of age, the obesity seen in childhood is noted to be resistant to change, leading to obesity in adulthood.4,95 This provides further evidence for the perinatal programming of obesity and emphasizes the significance of early life factors in the development of long-term obesity. This is a cause for concern, as obesity in later life is an important risk factor for many chronic disorders, such as cardiovascular diseases, hypertension, stroke, type 2 diabetes mellitus, as well as osteoarthritis.36 Besides these factors, being obese in early childhood confers a higher risk of multiple cardiometabolic comorbidities in adulthood, even if the obesity does not persist. If the current trend of childhood obesity continues, researchers propose that the current generation of children will have a shorter life-span than their parents due to childhood obesity and its associated complications.96

50.7.2.2 Metabolic Syndrome The basis of metabolic syndrome revolves around the excess energy and mishandling of stored excess energy, resulting in visceral adiposity. This leads to the metabolic derangements seen in metabolic syndrome.87 In adults, metabolic syndrome is defined as a constellation of symptoms encompassing abdominal obesity, hypertension, hyperglycemia, and dyslipidemia that occur simultaneously and increase the risk of ischemic heart disease, stroke, and fatty liver. Dyslipidemia is characterized by hypertriglyceridemia, as well as a reduced level of high density lipoproteins (HDL). The definition of metabolic syndrome in children is fraught with difficulties. Often, the diagnosis is derived from the adult definition, using children percentiles for the features described in the adult definition. However, there is a lack of consensus on its definition in children, with different cutoffs used.97 This is a major issue, as this definition of metabolic syndrome in children is not outcome-based, unlike the adult definition which is based on the outcome of cardiovascular disease and diabetes.96

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Despite the difficulty in defining metabolic syndrome in children, it is important to identify these children, as there is emerging evidence that metabolic syndrome tracks into adulthood, leading to nearly twofold increased risk of death by ischemic heart disease in adulthood.97,98 Components of metabolic syndrome are prevalent in children and seen as early as 5 years of age.97 Overall growth in early childhood forms the basis of body composition in adulthood.99 The amount and location of fat deposition in early childhood affect the cardiometabolic risk profile in adulthood, with higher fat deposition, especially in the visceral region rather than the subcutaneous area conferring the highest risk.98 With the continuous accumulation of fat, there is increased insulin resistance by skeletal muscle, as well as reduced glucose utilization and insulin degradation by the liver, leading to hyperglycemia as well as hyperinsulinemia and ultimately metabolic syndrome. A recent review99 found that obesity in the first 6 years of life is associated with nearly 1.5 times increased risk of metabolic syndrome in an adult. The effect of early childhood obesity on the risk of metabolic syndrome in adulthood increases with increasing age of the child with obesity. Two to six years of life appears to represent the most critical and sensitive time, whereby obesity at this age confers the highest risk of metabolic syndrome in adulthood.99 Rapid weight gain in infants in the first 2 years of life rather than weight itself was found to increase the risk of metabolic syndrome in adulthood.100

50.7.2.3 Insulin Resistance Insulin resistance is found to be the common denominator of the pathogenesis of the cardiovascular and metabolic complications of obesity. Childhood obesity is associated with reduced insulin sensitivity, which persists into adulthood causing type 2 diabetes mellitus.95,97 Excess deposition of fat, especially in the intra-abdominal visceral region, leads to increased secretion of proinflammatory cytokines, as well as increased circulatory free fatty acid, which promotes insulin resistance in the liver and skeletal muscle. Similar to the definition of metabolic syndrome in children, there is a lack of consensus in defining insulin resistance in children, ranging from using fasting insulin levels to using homeostasis model of assessment of insulin resistance (HOMAIR) with varying cut offs.97 Unsurprisingly, this leads to wide variations in the reporting of the prevalence of insulin resistance in children, from 5% to 72%, depending on the definition used.97 Despite this, it is crucial to identify children with insulin resistance, as this is the initial step in the pathogenesis of type 2 diabetes mellitus. The compensatory hyperinsulinemia from insulin resistance leads to impaired early insulin secretion, causing initially postprandial and then fasting hyperglycemia.98 Type 2 diabetes mellitus is no longer a disease of adulthood, but is quickly becoming a serious problem in pediatrics with the prevalence of 15%–20% in children and seen as early as 6 years of age.98

50.7.2.4 Cardiovascular Atherosclerosis begins early in childhood.97 There is a higher risk of endothelial dysfunction, a key step or atherosclerosis, in early childhood obesity, which ultimately leads to hypertension.98 Atherosclerosis is accelerated by dyslipidemia found in obesity with an increased level of triglyceride and reduced level of high density lipoprotein cholesterol. This may be due to either the direct effect of the dyslipidemia itself or the diet associated with dyslipidemia. Insulin resistance associated with early childhood obesity also contributes to hypertension by increasing renal sodium retention, increasing sympathetic activity, as well as increased vascular smooth muscle growth.97 These put extra strain on the cardiovascular system, leading to left ventricular hypertrophy and cardiovascular diseases.

50.7.2.5 Nonalcoholic Fatty Liver Disease Accumulation of macrovesicular fat may also occur in the hepatocytes of up to 70% of obese children, leading to nonalcoholic fatty liver disease (NAFLD).97 NAFLD shares many similarities with metabolic syndrome and is often described as a hepatic manifestation of metabolic syndrome.97 Although commonly asymptomatic, initially apart from palpable hepatomegaly in some cases, NAFLD may progress into nonalcoholic steatohepatitis (NASH), which is a progressive form of NAFLD that ultimately leads to liver fibrosis, cirrhosis, hepatocellular carcinoma, as well as liver failure requiring a liver transplant in adulthood.98 Because of its typical asymptomatic presentation, screening for this condition in obese children is crucial.

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50.7.2.6 Respiratory Disorders Children with obesity often suffer from restrictive lung diseases due to the strain that the excess weight has on the lungs. Nearly a third of overweight and obese children have some form of obstructive sleep apnea,96 with an increased risk of up to six times in obese children.98 Obstructive sleep apnea is disordered breathing during sleep with prolonged partial upper airway obstruction and/or intermittent complete airway obstruction, disrupting normal breathing pattern during sleep and the sleeping pattern.98 As a result, the child will snore and have disturbed sleep. This, in turn, causes daytime tiredness, which may cause neurobehavioral problems and reduce the physical activity of the child, creating a vicious cycle and making it difficult to control obesity. Besides, the strain that obstructive sleep apnea places on the heart leads to pulmonary hypertension and its associated cardiorespiratory long-term complications. Children with obesity often have increased incidence of asthma and asthmatic attacks. As a result, this reduces the exercise tolerance of the child, limiting the child’s physical activity. However, the biological mechanism for this association is unclear at present. It is uncertain if childhood obesity causes asthma or makes the severity of an asthmatic attack worse.

50.7.2.7 Orthopedic Disorder The effect of weight placed onto the developing skeletal system in obese children leads to various orthopedic growth plate disorders, such as fracture, slipped upper femoral epiphysis (SUFE), and tibia vara, which is known as the Blount disease eponymously.96 SUFE is a growth plate disorder that commonly occurs in obese male adolescents. The growth plate of the femur head is displaced from the femur, causing hip and knee pain on walking as well as limited hip internal rotation movement.98 Tibia vara is a mechanical deficiency of the medial tibial growth plate. As a result, the growth of the medial aspect of the proximal tibial growth plate is disordered, causing pain at the medial aspect of the knee and lower limb deformity such as “bow leg”.98

50.7.2.8 Psychological Impact Childhood obesity has a significant psychological impact on the mental health of children. Teasing and bullying are commonly reported by obese children, leading to negative self-image, reduced self-esteem, and social skills. This, in turn, may cause poor educational and financial attainment in later life, as well as mental health disorders such as depression and suicide.98 Besides this, childhood obesity is also found to lead to loss of control in eating, unhealthy extreme weight control behaviors, and ultimately eating disorders.98

50.8 CONCLUSION The increasing obesity epidemic seen currently may be partly explained by environmental insults, especially malnutrition, in the early life period. The timing and intensity of such events play a significant role in the perinatal programming of obesity. The perinatal period is a sensitive interval for development and programming of the hypothalamus-adipose axis. Various environmental insults with opposing effects, such as overnutrition and undernutrition during the perinatal period, lead to a similar outcome in offspring. This suggests a potential common programming mechanism. However, little is known of the biological mechanism by which the adverse perinatal environment modifies the appetite regulatory pathway and body weight set points, thereby causing obesity in later life. A better understanding of the biological mechanism is needed to help identify early modifiable determinants of obesity in later life. These determinants can then be used to develop intervention strategies during pregnancy and the early postnatal period to prevent obesity and metabolic disorders in adulthood. The perinatal programming of obesity is a complex pathway. Hence the interventions to tackle obesity should take into account the complexity of the issue. Attempts to simply alter the energy intake or expenditure in infants may be ineffective, especially in infants who are already programmed by circulating factors and epigenetic modifications to gain weight in a certain trajectory. Interventions proposed should also be tailored to different populations, such as preterm infants or infants in developing countries where undernutrition and growth stunting are still common. For example, future studies should explore the impact of proposed interventions on the competing risks of neurodevelopment and cardiometabolic disorders in the preterm infants. This is less of a problem in term infants because weight gain has less of an impact on neurodevelopment compared with preterm infants. Postnatal weight gain is a significant predisposing factor for obesity in later life. However, there is no consensus on the optimum weight gain that should be achieved by the different infant populations exposed to perinatal insults. Apart from

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this, a better measure of obesity in infants is needed in the clinical and research settings. Weight alone is no longer an acceptable measure of obesity in infants. At the very least, weight for length should be measured and can be used in clinical practice. Despite this, it does not provide a true reflective measure of adiposity. Hence it does not provide sufficient information in the research setting to explore the biological mechanisms and determinants of perinatal programming of obesity. Longitudinal body composition, and the distinction between the fat as well as the fat-free mass, are crucial in accurately assessing obesity in infants. This will undoubtedly provide more information on the perinatal programming of obesity.

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