Obesity, Metabolic Syndrome, and Nutrition

Introduction

Over the last few decades, childhood obesity rates have increased globally. Childhood obesity is a serious health concern putting the child’s long-term health and quality of life at risk. Children with obesity are at greater risk of developing related metabolic and psychological conditions, and experiencing pervasive weight bias and stigma. Childhood obesity tracks into adolescence and adulthood, and is strongly correlated with risk of poor adult health, with considerable social and economic outcomes. The most common cause of obesity in children is a positive energy balance due to caloric intake in excess of caloric expenditure and decreased levels of physical activity combined with a genetic predisposition for weight gain. A large and growing body of evidence supports the concept of developmental programming through which the maternal environment affects fetal and infant development, thereby altering the risk profile for disease later in life. Maternal obesity during pregnancy predisposes to a higher prevalence of obesity in the offspring. Previous data have shown that obese women produce milk with increased concentrations of leptin, insulin, and C-reactive protein compared with normal weight counterparts, which may influence their child’s body weight. Maternal BMI may also be associated with the sugar composition in their milk. Insights on the unique milk metabolome profiles characteristic of maternal obesity and the potential impact of differentially abundant milk metabolites, including human milk oligosaccharide concentrations, which are associated with fat mass in the infant, have been provided by two of the studies reviewed below. Early life nutrition has a significant impact on lifelong health. Human milk is the gold standard source of nutrition in infancy as it is specifically tailored to support the growth and development of the infant. Nutrition during the first years of life also seem to play an important role in the occurrence of childhood obesity and the development of cardiometabolic risk, as documented in some of the manuscripts reviewed below. Introducing complementary foods other than breastmilk or formula can acutely change the infant’s gut microbiota composition. One of the studies evaluated the potential interaction between timing of infant complementary feeding and breastfeeding duration in the determination of early childhood gut microbiota composition and BMI in early childhood. Another study examined the nutrition- and feeding practice-related risk factors for rapid weight gain during the first year of life. High protein intake in early life may be associated with an increased risk of childhood obesity. One of the reviewed studies evaluated the impact of different levels of protein intake by infants on blood metabolic and hormonal markers and the association between these markers and anthropometric parameters and body composition until the age of 2 years. The results demonstrated that reduction of the protein intake by 20% did not result in a different metabolic profile in formula-fed infants in the first months of life.

Some studies have shown that school environments that support healthy food and physical activity behaviors may positively influence childhood obesity. A few of the reviewed studies tried to evaluate the impact of the diet composition (as adherence to high protein/low glycemic index diet or the Mediterranean diet) on insulin resistance and metabolic syndrome among children and adolescents with overweight or obesity. One large study assessed whether interaction effects occur between an obesity genetic risk score and the adherence to a Mediterranean diet on adiposity and metabolic syndrome. Other study results showed that the inclusion of dairy foods in the diet of adolescent females with overweight/obesity, as part of a diet and exercise intervention, favorably improved body composition even in the absence of weight loss. Higher consumption of dairy products, particularly low-fat milk and yogurt, was associated with reduced risk of incident metabolic syndrome. Children with obesity are prone to develop obesity-related comorbidities. One of the main comorbidities is non-alcoholic fatty liver disease (NAFLD). The role of genetic predisposition and nutrition and diet in the development of NAFLD is still not fully understood. Current data found that higher sugar-containing beverage intake in infancy was associated with NAFLD in school-aged children, independent of sugar-containing beverage intake and BMI at school age. Recent literature suggests that also the Western diet’s imbalance between high ω-6 (n-6) and low ω-3 (n-3) polyunsaturated fatty acids (PUFA) intake contributes to NAFLD in obese youth. Data from one of the studies demonstrated that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with NAFLD. Considering the deleterious consequences of obesity in childhood, public health interventions are urgently called for to promote an active lifestyle with engagement in physical activity and to take nutritional measures with policies that encourage healthy eating among children. In this chapter we review a selection of 14 notable articles published between
July 2020 and June 2021, focusing on the relation between nutrition, obesity, and metabolic comorbidities in childhood and young adulthood.

Maternal Weight during Pregnancy and Risk of Childhood Obesity

Maternal adiposity alters the human milk metabolome: associations between non glucose monosaccharides and infant adiposity

Comments: The “first 1,000 days” of a child’s life, beginning at conception and ending on their second birthday, has been identified as an important period for the establishment of obesity and associated diseases affecting life-long health. To date, several studies have characterized a large number of risk factors able to positively or negatively affect a rapid weight gain. Of note, all these factors might operate both before and during pregnancy as well as early in life. Among them certainly maternal breastfeeding during the same period has been shown to be negatively associated with rapid weight gain. Thus, exclusive breastfeeding is recommended for all infants for the first 6 months of life. However, further studies have also shown that factors related to maternal weight and particularly maternal pre-pregnancy overweight and excessive maternal gestational weight gain, as well as maternal and paternal overweight, are also associated with a greater risk of increased weight in the infant. Therefore, it is important to understand differences in human milk composition that may have an impact on infant growth and development. Maternal weight might affect human milk composition, thus affecting growth during early infancy. Therefore, an “omic” approach to human milk composition and particularly the human milk metabolome, defined as the complete set of low molecular weight metabolites, might offer novel insights in the mechanisms through which maternal body weight might affect weight gain in breastfed infants. In this study, the authors were able to perform a secondary analysis of normal weight (BMI: 18.5–24.9) or obese (BMI: 30–65) breastfeeding participants (172 mother-child pairs) that were enrolled in 2 parent longitudinal studies with the aim to identify unique milk metabolome profiles characteristic of maternal adiposity using an untargeted metabolomics analysis of human milk. In detail, the authors reported a unique metabolic profile throughout the first 6 months postpartum in human milk from obese women compared to non-obese mothers.

In particular, the authors showed that, compared with human milk from normal weight women, maternal increased adiposity during pregnancy is associated with a human milk metabolome characterized by an enriched amount of monosaccharides and sugar alcohols. In addition, over the first 2 months postpartum, relative amounts of human milk monosaccharides (mannose and ribose) and sugar alcohols (lyxitol and ribitol) were positively correlated with maternal BMI and fat mass. Also, human milk mannose, lyxitol, and shikimic acid showed a significant positive association with infant adiposity during the first 6 months postpartum that became stronger when only exclusively breastfed infants were considered. Human milk is the gold standard source of nutrition in infancy as it is specifically tailored to support the growth and development of the infant. Human milk is composed of macronutrients, abundant micronutrients, and bioactive molecules, which can change over lactation and can vary considerably between individuals. Therefore, further studies characterizing all aspects of maternal biology and the environment that can impact milk production and particularly composition are urgently needed in order to properly impact the growth and development of breastfed infants during a crucial time of life.

In addition, further studies elucidating the mechanisms leading to a rise in human milk metabolites from obese women and the complete mechanisms by which these metabolites affect growth in infants is needed in order to completely define the association between maternal adiposity and the risk of obesity in early childhood.

Breastfeeding and Nutrition during Early Life and Risk of Childhood Obesity

Human milk oligosaccharide concentrations and infant intakes are associated with maternal overweight and obesity and predict infant growth

Comments: Human milk certainly represents the gold standard nutrition during infancy and is positively associated to infant growth and childhood development. More importantly, human milk has been shown to have health benefits for both mother and child, including reduced risk for developing obesity in the offspring. During the last decades, new technologies have drastically improved our ability to define in different biological samples specific molecules which might play a key function in human biology.

In this respect, high-performance liquid chromatography of human milk is able to define several macronutrients, micronutrients, and bioactive molecules which contribute to its positive effects. In this study, the authors were able to cluster individual human milk components and particularly were able to cluster its peculiar changes induced by maternal adiposity during pregnancy and to define its association to infant growth over the first 6 months of life. In particular, by performing a high-performance liquid chromatography on an Amide-80 column with fluorescence detection, the authors were able to measure the concentrations of 19 human milk oligosaccharides and to evaluate daily infant human milk oligosaccharide intakes. In addition, by defining human milk oligosaccharides in samples collected at 2 months postpartum from three groups of women with different weight degrees (normal weight, overweight, and obese during pregnancy), the authors showed that maternal obesity is associated with significant changes in concentrations of several fucosylated
and sialylated human milk oligosaccharides.

Interestingly, by evaluating auxological data, the authors were also able to show a significant effect of changes in human milk oligosaccharides concentrations on infant growth and adiposity. Particularly, decreasing concentrations of sialylated/acidic HMOs with increasing maternal BMI may provide protective mechanisms via human milk intake against excess weight gain and adiposity in offspring.
These data suggest that some peculiar human milk oligosaccharides may be promising targets for future work in human milk nutritional programming. Further data characterizing these peculiarities are needed in order to provide solid evidence of additional factors that characterize the relationship between infant growth and both exposure to different degrees of maternal BMI and human milk oligosaccharides during the first months of life.

Nutrition- and feeding practice-related risk factors for rapid weight gain during the first year of life: a population-based birth cohort study

Comments: The alarming data on the drastic effects of the COVID-19 pandemic on the prevalence of childhood obesity and overweight in all age groups have clearly shown the urgent need of effective prevention strategies to address this significant health and economic burden. Particularly, preventive strategies need to contrast all risk factors associated with obesity during childhood. Among them, one identified risk factor widely studied and characterized during the last decade is rapid weight gain. In fact, an upward centile crossing in weight growth charts, defined as a change >0.67 in weight standard deviation scores during the first 2 years of life, is clearly associated with overweight or obesity later in childhood and adulthood. Therefore, the characterization of all those nutrition and feeding practice-related risk factors associated with a rapid weight gain during this period is of relevance in order to activate precise preventive strategies.

According to this issue, in this study the authors were able to evaluate data from a longitudinal birth cohort study, an ongoing population-based birth cohort study – the Halland Health and Growth Study. This study included 2,666 infants at baseline, 1,349 boys and 1,317 girls, born in the county of Halland in south-western Sweden, between October 1, 2007 and December 31, 2008. In particular, by analyzing the data available for 1,780 infants classified as having a rapid weight gain or not during 0–3– 4, 0–6, and 6–12 months, the authors were able to show that the first 6 months of life are critical for the development of rapid weight gain in infants. Interestingly, the most relevant and independent factors able to positively affect changes in body weight during this crucial period are bottle-feeding and nighttime meals containing formula milk. In contrast, during the same period they documented that breastfeeding is a protective factor.

Therefore, these results clearly show not only a relevant time period for preventive intervention strategies but also two relevant key factors to be modified as much as possible in order to minimize or fully contrast the rapid weight gain. In addition, the results of this study lay the ground for further studies evaluating the best feeding practice from a bottle in order to avoid rapid weight gain during the first 6 months of
life.

Potential interaction between timing of infant complementary feeding and breastfeeding duration in determination of early childhood gut microbiota composition and BMI

Comments: During the last decade a large number of studies have shown that childhood overweight and obesity are linked to adverse health outcomes throughout the lifespan. Particularly, overweight and obese children are more likely to become obese adults and have a greater risk of metabolic, pulmonary, and cardiovascular diseases, including diabetes, hypertension, stroke, and asthma. Childhood obesity diminishes social and emotional functioning, including depression, bullying, and low self-esteem. Therefore, there is need to identify modifiable early-life determinants of increased adiposity, particularly already during infancy.

Among these determinants, the timing of introduction of complementary foods, particularly at the time of introducing foods other than breastmilk or formula, might play a relevant role. In fact, introduction of complementary feeding before 4 months of
age is associated with a greater risk of childhood overweight and obesity, independently of breastfeeding status at the time of solid food introduction. Although it might be postulated that early complementary feeding might influence differential growth and metabolism of gut microbiota, thus affecting the risk of obesity, few studies have clearly shown this link. Therefore, in this study the authors evaluated data from the Canadian birth cohort, named the Genetics of Glucose Regulation in Gestation and Growth (Gen3G), originally designed to elucidate the biological, environmental, genetic, and epigenetic determinants of glucose regulation during pregnancy and the impact on offspring development. Using a relatively large study population, the authors were able to investigate associations of early compared to
later introduction of complementary foods with the composition and diversity of gut microbiota in childhood. In particular, the authors showed that early introduction to complementary foods in infancy, while breastfeeding or not, was associated with a differential abundance of several metabolically active microbial taxa in the gut microbiota of children at 5 years of age. In addition, a higher childhood Z-BMI was associated with early infant complementary feeding, but only among children that were breastfed when early complementary foods were introduced. Therefore, this link suggests the need to further identify gut microbiota features associated with early complementary feeding, which in turn could at once elucidate the underlying mechanism linking early introduction of complementary foods with childhood obesity. These aspects are urgently desired in order to provide novel intervention targets for prevention of early increased adiposity in youth.

Complementary feeding and overweight in European preschoolers: the ToyBoxstudy

Comments: One of the risk factors for childhood obesity is the inappropriate nutrition during infancy and the first years of life. The advantages of exclusive breastfeeding compared to partial breastfeeding in the first months of life have been recognized. The World Health Organization’s global public health recommendations promote exclusive breastfeeding for 6 months with continued breastfeeding up to the age of 2 years or beyond. The recommended period for starting complementary feeding (CF) is between the 5th to 7th month of life [1]. However, there are still controversies about he possible relationship between the timing of introduction of solid foods (SF),
breastfeeding status, and obesity in childhood.

A recent study from the USA showed that feeding typified by predominant breastfeeding and delaying the introduction of CF after 4 months reduces the odds of rapid increases in weight-for-age Z-score and weight-for-length Z-score in the first year of life [2]. The current study was designed to investigate the association of the timing of CF, breastfeeding, and overweight in a large sample of preschool children. The results demonstrated that there was a positive association between the timing of SF introduction and duration of breastfeeding, as well as the socioeconomic status; breastfed children throughout the first 4–6 months of life and after the 12th month had a lower prevalence of overweight/obesity in childhood compared to formula-fed children. No significant risk to become overweight was observed among preschoolers who were introduced to SF at 1–3 months of age compared to those introduced at 4–6 months regardless of the type of milk feeding. Similarly, no significant association was observed between the early introduction of SF and risk for overweight in preschoolers
who were breastfed for ≥4 months or were formula fed. The strengths of the study are the large cohort of participants (n = 6,800) with inclusion of children from several European countries. The limitations of the study include the cross-sectional design, which does not enable identifying cause-effect associations, and the potential recall bias since data about weight, height, gestational weight gain, infant birth weight, breastfeeding practices, and timing of CF introduction relied on parental self-reporting by mothers a few years later. Also, since data relied on the European population, it cannot be generalized and implicated for other countries with a lower socioeconomic status, especially underdeveloped countries. Finally, we can conclude that based on this study there is no significant association between the timing of introducing CF and obesity in childhood. Yet, health professionals should emphasize the benefits of breastfeeding during the first months of life, especially to mothers who are less likely to follow recommendations. There is need for more prospective studies that should examine whether guidelines for SF introduction timing need to distinguish between exclusively breastfed infants, formula fed infants, and those who ceased exclusive breastfeeding too early.

References
1 Fewtrell M, Bronsky J, Campoy C, Domellöf M, Embleton N, Fidler Mis N, et al. Complementary feeding: A position paper by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on nutrition. J Pediatr Gastroenterol Nutr. 2017;64:119–32.
2 Wood CT, Witt WP, Skinner AC, Yin HS, Rothman RL, Sanders LM, et al. Effects of breastfeeding, formula feeding, and complementary feeding on rapid weight gain in the first year of life. Acad Pediatr. 2021;21:288– 96.
3 Lind MV, Larnkjær A, Mølgaard C, Michaelsen KF. Dietary protein intake and quality in early life: impact on growth and obesity. Curr Opin Clin Nutr Metab Care. 2017;20:71–6.
4 Marshall TA, Curtis AM, Cavanaugh JE, Warren JJ, Levy SM. Child and adolescent sugar-sweetened beverage intakes are longitudinally associated with higher body mass index z scores in a birth cohort followed 17 years. J Acad Nutr Diet. 2019;119:425–34.
5 Malik VS, Pan A, Willett WC, Hu FB. Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98:1084–102.
6 Millar L, Rowland B, Nichols M, Swinburn B, Bennett C, Skouteris H, et al. Relationship between raised BMI and sugar sweetened beverage and high fat food consumption among children. Obesity. 2014;22:96–103.
7 Mena-Sánchez G, Becerra-Tomás N, Babio N, Salas-Salvadó J. Dairy product consumption in the prevention of metabolic syndrome: a systematic review and metaanalysis of prospective cohort studies. Adv Nutr. 2019;10(Suppl 2):S144–53.
8 Boon N, Hul GB, Stegen JH, Sluijsmans WE, Valle C, Langin D, et al. An intervention study of the effects of calcium intake on faecal fat excretion, energy metabolism and adipose tissue mRNA expression of lipid-metabolism related proteins. Int J Obesity. 2007;31:1704– 12.
9 Lorenzen JK, Nielsen S, Holst JJ, Tetens I, Rehfeld JF, Astrup A. Effect of dairy calcium or supplementary calcium intake on postprandial fat metabolism, appetite, and subsequent energy intake. Am J Clin Nutr. 2007;85:678–87.
10 Bucher HC, Cook RJ, Guyatt GH, Lang JD, Cook DJ, R Hatala, et al. Effects of dietary calcium supplementation on blood pressure. A meta-analysis of randomized controlled trials. JAMA. 1996;275:1016–22.
11 Dugan CE, Fernandez ML. Effects of dairy on metabolic syndrome parameters: a review. Yale J Biol Med. 2014;87:135–47.
12 Waters E, de Silva-Sanigorski A, Hall BJ, Brown T, Campbell KJ, Gao Y, et al. Interventions for preventing obesity in children. Cochrane Database Syst Rev. 2011;12:CD001871.
13 Notario-Barandiaran L, Valera-Gran D, Gonzalez-Palacios S, Garcia-de-la-Hera M, Fernández-Barrés S, Pereda- Pereda E, et al. High adherence to a mediterranean diet at age 4 reduces overweight, obesity and abdominal obesity incidence in children at the age of 8. Int J Obes. 2020;44:1906–17.
14 Ma J, Fox CS, Jacques PF, Speliotes EK, Hoffmann U, Smith CE, et al. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts. J Hepatol. 2015;63:462–9.
15 Ayonrinde OT, Oddy WH, Adams LA, Mori TA, Beilin LJ, de Klerk N, et al. Infant nutrition and maternal obesity influence the risk of non-alcoholic fatty liver disease in adolescents. J Hepatol. 2017;67:568–76.
16 Schwimmer JB, Ugalde-Nicalo P, Welsh JA, Angeles JE, Cordero M, Harlow KE, et al. Effect of a low free sugar diet vs usual diet on nonalcoholic fatty liver disease in adolescent boys: a randomized clinical trial. JAMA. 2019;321:256–65.
17 Toshimitsu K, Matsuura B, Ohkubo I, Niiya T, Furukawa S, Hiasa Y, et al. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition. 2007;23:46– 52.

18 Parker HM, Johnson NA, Burdon CA, Cohn JS, O’Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;56:944–51.
19 Feldstein AE, Lopez R, Tamimi TA, Yerian L, Chung YM, Berk M, et al: Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Lipid Res. 2010;51:3046–54.
20 Li J, Hua W, Ji C, Rui J, Zhao Y, Xie, et al. Effect of the patatin-like phospholipase domain containing 3 gene (PNPLA3) I148M polymorphism on the risk and severity of nonalcoholic fatty liver disease and metabolic syndromes: a meta-analysis of paediatric and adolescent individuals. Pediatr Obes. 2020;15:e12615.
21 Tang S, Zhang J, Mei TT, Guo HQ, Wei XH, Zhang WY, et al. Association of PNPLA3 rs738409 G/C gene polymorphism with nonalcoholic fatty liver disease in children: a meta-analysis. BMC Med Genet. 2020;21:163.