Obesity, Metabolic Syndrome, and Nutrition

Shlomit Shalitin
Luis A. Moreno

The childhood obesity pandemic is currently being observed in most developed and developing countries and urges the identification of effective strategies for its prevention and treatment. Childhood obesity tracks into adolescence and adulthood, resulting in an increased risk of diseases (e.g., cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver disease [NAFLD], cancer), and premature death. 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 to 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 and gestational diabetes are associated with childhood obesity. Prenatal intrauterine environment has also been thought to play an important role in childhood obesity. Insights on the potential impact of maternal gestational diabetes and maternal diet content during early life on childhood adiposity have been provided by two of the studies reviewed below.

Also, breastfeeding and the nutrition during the first years of life seem to play an important role in occurrence of childhood obesity and cardiometabolic risk development as documented in some articles reviewed below. One of the studies found associations of early complementary feeding introduction with adiposity measurements in breastfed and formula- fed children from mid-childhood through early adolescence, with stronger associations seen in formula-fed children.

Milk is a significant source of calories and nutrients in the diets of young children. Milk consumption is associated with better diet quality in children and a higher likelihood of meeting nutrient requirements. The American Academy of Pediatrics and American Heart Association recommend low-fat or reduced-fat varieties in place of whole (4%) milk for those aged 2 years and older. However, recent data based on observational studies supports that children who consume whole milk compared with reduced-fat milk have lower odds of overweight or obesity.

Diet and physical activity are lifestyle determinants of health, closely related to obesity and its complications. Nowadays, nutrition research focuses on examining the impact of dietary patterns such as the Mediterranean diet (MD) on health outcomes. Recent findings suggest that metabolically healthy obese adolescents have a higher adherence to the MD compared to metabolically unhealthy obese adolescents, which might be mainly due to a higher fish intake, supporting the possible preventive role of the MD and its components in the metabolic syndrome development. Fast food intake is another eminently modifiable risk factor for excess weight gain. Fast food intake is associated with greater total caloric, fat, and added sugar intakes. One of the reviewed studies that included a large cohort of preschool-age children reported that children who ate fast food more frequently over a 1-year period were more likely to increase their weight status during that time. Children with obesity are prone to develop obesity-related comorbidities. One of the comorbidities is NAFLD. The role of genetic predisposition and nutrition and diet in the development of NAFLD is still not fully understood. Some studies presented in this chapter indicate the roles of genetic predisposition (patatin-like phospholipase domain-containing gene), parental obesity, postnatal diet, and lifestyle in the development and progression of NAFLD.

Obese children also have a higher risk of vitamin D deficiency and systemic inflammation. Vitamin D deficiency in children is associated with markers of poor cardiometabolic health, and with markers of subclinical arteriosclerosis that are predictors for future cardiovascular events. One of the studies reports that vitamin D supplementation in overweight and obese vitamin D-deficient children resulted in lowering of blood pressure and improvements in insulin sensitivity. Thus, vitamin D status optimization may have a primary preventive role in improving the long-term cardiovascular health of obese children. Finally, the worldwide COVID-19 pandemic in the last year brought individual and collective protection measures to contain the expansion of its transmission, such as social distancing and lockdown. In addition to economic and social instability, the lockdown can affect the food supply chain and nutrition with decreased physical activity. Obesity rate may increase due to more sedentary lifestyle and change in food purchasing, eating behaviors, and perceptions of food safety. The higher consumption of processed foods with higher caloric content, high in saturated fats, sugars, and refined carbohydrates, greater durability, easier access and use especially in children, can contribute to increased prevalence of obesity in the times of COVID-19 pandemic. Considering the deleterious consequences of obesity in childhood, which can enhance during social isolation and lockdown, public health interventions are urgently called to promote an active lifestyle with engagement in physical activity and to take nutritional measures with policies that encourage healthy eating among children to mitigate the adverse impact of COVID-19 on unhealthy weight gains and childhood obesity. In this chapter, we review a selection of 14 notable articles published between July 2019 and June 2020, focusing on the relation between nutrition, obesity, and metabolic comorbidities in childhood and young adulthood.

Maternal Diet during Pregnancy and Risk of Childhood Obesity

Associations of maternal caffeine intake during pregnancy with abdominal and liver fat deposition in childhood

Comments: There is compelling human and animal evidence supporting the “fetal programming” hypothesis, according to which in utero exposure permanently alters an organism’s physiology and metabolism, leading to susceptibility to subsequent disease, including obesity and metabolic disorders [1]. Consumption of caffeine-containing beverages during pregnancy has been related to an increased risk of fetal death and impaired fetal growth. In addition, maternal caffeine intake during pregnancy may also
influence long-term offspring body fat development with an increased risk of obesity in childhood [2, 3]. However, it is not known whether maternal caffeine intake during pregnancy is also related to offspring abdominal and liver fat accumulation. In line with previous studies, in the current population-based prospective cohort study, high maternal caffeine intake during pregnancy was associated with long-term consequences for offspring body fat development, as reflected by higher total body fat mass, abdominal fat mass, and liver fat fraction at the age of 10 years. The strongest effects were present for maternal caffeine intake during pregnancy of ≥4 units per day.

As visceral and liver fat accumulation are related to the development of cardiometabolic disease independently of total body fat, these children might be also at risk of
later cardiometabolic disease. Suggested mechanism supporting the association between caffeine consumption during pregnancy and offspring obesity can be provided by animal studies, where prenatal exposure to caffeine was shown to program the offspring towards excess growth and cardiometabolic disorders through alterations in the hypothalamic-pituitary-adrenocortical axis that plays a key role in growth and metabolism [4] and in the placental expression and transportation of leptin [5] essential for appetite regulation. The strengths of the current study are the large population-based cohort from early pregnancy onwards, enabling to prospectively study the associations of interest. The limitations include: the data about maternal caffeine intake that was based on questionnaires, and might have been underreported, possibly leading to misclassification of the caffeine intake categories and underestimation of the effect estimates. Another limitation is the absence of data about other potential confounders that were not evaluated and may have an impact on the results, such as maternal and child’s physical activity and dietary habits.


Gestational diabetes exposure and adiposity outcomes in childhood and adolescence: An analysis of effect modification by breastfeeding, diet quality, and physical activity in the EPOCH study

Comments: In general, it is considered that gestational diabetes is associated with increased adiposity [6]. A meta-analysis including results from more than 24,000 infants showed that infants of mothers with gestational diabetes had 62 g more fat mass (95% CI:29–94 g) than infants of mothers without gestational diabetes [7]; the difference was higher in boys than in girls. In addition, in a study including more than 200,000 families, the BMI of boys from mothers having gestational diabetes was 0.94 kg/m2 higher (range from 0.35 to 1.52) than in their brothers born before their mother developed gestational diabetes [8]. However, there is little information on whether lifestyles during childhood may attenuate the effect of gestational diabetes on excess body fat deposition.

The current study assessed the association of gestational diabetes and adiposity in children and adolescents aged 6–19 years, considering the potential effect of diet and physical activity behaviors. They observed that gestational diabetes was associated with increased BMI and subcutaneous adipose tissue, but only among those with a low Healthy Eating Index score and those with ≤1 h of vigorous activity per day. Both diet and physical activity were self-reported and then susceptible to be influenced
by social desirability in the parent’s responses. Diet was assessed using a semiquantitative food frequency questionnaire. Despite these limitations, it seems that behaviors during childhood, especially a healthy diet, are able to attenuate the association between gestational diabetes and excess adiposity later during childhood and


Breastfeeding and Nutrition during Early Life and Risk of Childhood Obesity

Association of breastfeeding and early exposure to sugar-sweetened beverages with obesity prevalence in offspring born to mothers with and without gestational diabetes mellitus

Comments: Many prenatal and early life factors such as in utero exposure to gestational diabetes mellitus (GDM) and early life infant feeding may contribute to higher weight gain, obesity, and related metabolic complications in children [9, 10]. The evidence points to sugar consumption, in particular sugar-sweetened beverages (SSBs), as a key modifiable factor contributing to obesity and related metabolic disorders [11]. Therefore, the goal of the current study was to examine the individual and interaction effects of exclusive breast feeding (EBF), SSB intake, and GDM status on obesity prevalence in offspring. This study shows that being exposed to GDM in utero is a contributing factor to childhood obesity. The current study found that GDM offspring had 1.72 times higher odds of obesity than non-GDM offspring. Exposure to maternal diabetes is associated with excess fetal growth in utero, possibly due to fetal hormonal alterations (elevated leptin synthesis, hyperglycemia, and hyperinsulinemia) and perturbations in fetal fat accretion. The current study found a significant interaction effect of GDM and EBF on obesity prevalence and showed that within GDM offspring, those who were EBF compared with those not EBF had 44% lower odds of obesity prevalence. The current study findings also showed that children who were EBF for at least 6 months and had low SSBs intake (≤1 serving/day) had lower odds of obesity than those with high SSBs intake (>3 servings/day) regardless of GDM status of their mothers throughout pregnancy. Therefore, exposure to GDM and high SSB intake are independently associated with higher risk of obesity, whereas EBF is independently associated with lower risk of obesity. Within GDM offspring, EBF is only associated with lower obesity levels if SSB intake is also low, whereas EBF is protective against obesity in non-GDM offspring regardless of high or low SSB intake.

The limitations of the current study include the predominance of Hispanic participants in the study sample; therefore, the findings may not be applicable to other populations. EBF was retrospectively collected on children 1–5 years of age, while anthropometric measures of height and weight were collected on the children at a later visit, when the children were between 1 and 5 years of age. Also, the study did not account for GDM mothers receiving treatment, and the severity of the GDM was not known. There is also lack of data regarding maternal BMI and parity that may impact subsequent obesity and metabolic disease risk in the offspring. However, the results of the current study suggest that interventions should focus on the combined protective effects of EBF and low SSB intake particularly in GDM offspring.


Impact of lifestyle behaviors in early childhood on obesity and cardiometabolic risk in children: Results from the Spanish INMA birth cohort study

Comments: of a given genetic susceptibility in children exposed to a number of lifestyle risk factors. The individual factors are well characterized, but developing obesity or not is a matter of their additional effect or interaction. However, there is no clear evidence on how different lifestyle risk factors interact with each other. There are different strategies for studying the combined effect of the risk factors; probably the most widely used is cluster analysis. In the current article, the authors choose to construct a child healthy lifestyle score, considering five lifestyle behaviors; three positive behaviors: extracurricular physical activity, sleep time, and plant-based food consumption and two unfavorable behaviors: TV watching and consumption of what they consider as ultra-processed foods.

The association of the five lifestyle behaviors in children aged 4 years on obesity at age 4 and 7 years was estimated. At 4 years, children in the highest tertile of the score
had lower risk of overweight or obesity (OR = 0.61; 95% CI: 0.39–0.96) and abdominal obesity (OR = 0.48; 95% CI: 0.24–0.96) at the age of 7 years. The approach of summing up the five behaviors is of interest and showed a 39% risk reduction for obesity and 52% risk reduction for abdominal obesity. The score could be optimized by trying to weight the differential effects of every included factor. Definition and practical application of what are considered as ultra-processed foods is currently controversial. The argument for using it, is to avoid the consumption of fat, sugar, and salt. However, it seems difficult to have the general population classifying the foods according to the level of processing.

In conclusion, children cumulating lifestyle risk factors, like low levels of physical activity, short sleep duration, low consumption of fruits and vegetables, excess TV watching and high consumption of energy dense foods, have an increased risk of developing obesity later in life.


Timing of complementary feeding introduction and adiposity throughout childhood

Comments: Timing of complementary feeding has been suggested to influence the development of obesity during childhood and adolescence. Two previous systematic reviews concluded that early introduction of solid foods (≤4 months of age) was associated with a high BMI [12, 13]. Late introduction of complementary feeding, after 6 months, was not associated with overweight or obesity later in life [13]. The current study also addresses the association between the timing of complementary feeding and adiposity during childhood and adolescence in the Viva cohort. They assessed adiposity at a mean age of 7.9 and 13.2 years. Early complementary feeding (≤4 months of age) was associated with high adiposity at childhood, but only in breastfed children; in adolescence, it was associated with the sum of subscapular and triceps skinfolds, waist circumference, and truncal fat mass assessed by dual-energy X-ray absorptiometry, and the effect estimates were higher in formula-fed infants. Late introduction of complementary feeding (>6 months of age) was associated with the subscapular to triceps ratio, both in childhood and adolescence, but only in formula- fed children.

Concerning specific foods, they observed an association between early introduction of infant cereals and fruit juices and a high BMI z-score and waist circumference in childhood; for cereals, the association was observed both in breastfed and formulafed children, but for fruit juices it was only observed in breastfed children. To explain these specific associations, the authors hypothesize that for cereals, it might just be the introduction of foods in general, as cereals were the first foods introduced; for fruit juices, the impact of their early introduction might be related to a high intake of fruit juices during childhood and adolescence.

Limitations of the majority of studies in the previous systematic reviews [12, 13], are the small sample sizes, a lack of consideration of important confounders (such as breastfeeding or formula feeding), and the lack of longitudinal assessment of adiposity measurements. The main contribution of this current study is the sample size
which was quite large (1,013 children), the follow-up until a mean-age of 13.2 years, and the considerations of the main confounding factors such as socioeconomic status and the type of early feeding (breastfeeding vs. formula feeding). In terms of timing of complementary feeding recommendations, the results of the current study support the majority of recommendations, such as the one from ESPGHAN: “Complementary foods (solids and liquids other than breast milk or infant formula) should not be introduced before 4 months but should not be delayed beyond 6 months” [14].


Nutrition during Childhood and Risk of Childhood Obesity

Whole milk compared with reduced-fat milk and childhood overweight: A systematic review and meta-analysis

Comments: Until recently, dairy fat was often considered a negative component of milk and dairy products, and some authors have suggested an increased risk of obesity with frequent dairy consumption. Recently, it was observed that milk and dairy products consumption was neutral or inversely associated with adiposity in children and adolescents [15]. The current systematic review selected observational and interventional studies conducted in children aged 1–18 years, assessing the association between cow-milk fat consumption and the body mass index (BMI) z-score, as an index of adiposity. The authors did not find any interventional study. The majority of the studies (18 out of 28) observed a negative association. Meta-analysis performed with data from 14 studies measuring the proportion of children consuming whole milk compared with the proportion consuming low-fat milk and estimations of the proportion of children with overweight or obesity, observed a pooled odds ratio of 0.61 (95% CI: 0.52–0.72) but with a large heterogeneity between the studies. Therefore, the included observational studies point in the direction of lower adiposity in those children consuming whole instead of low-fat milk.

There are different potential explanations for the observed findings. First, when dairy fat is removed from the diet, it can be replaced by other energy-dense foods and beverages. Second, a satiety mechanism could be involved, as dairy fat may stimulate the secretion of cholecystokinin and glucagon-like peptide 1. Third, some fatty acids being part of milk and dairy products, such as trans-palmitoleic or conjugated linoleic acid have been shown to be associated with less adiposity. In addition, several confounding factors, related to the design of the observational studies should be considered, like confounding by indication and reverse causality; for instance, families of children with low adiposity may select to consume whole milk and dairy products and, at the opposite, those families of children with high adiposity may decide to consume low-fat milk and dairy products. An additional factor to be considered is the food matrix that could influence the effect of the milk components. For future research, randomized clinical trials should be conducted that will allow preventing bias related to the study design and give the opportunity to perform mechanistic explorations. In practical terms, the obtained results should be considered an argument for not recommending low-fat and dairy products for children from 2 years until the end of the adolescence.


Associations between milk fat content and obesity, 1999 to 2016

Comments: Among young children who drink milk, the association between milk fat content and later risk of obesity is yet unclear. Previous studies based on the early childhood longitudinal study, birth cohort, a representative sample of US children found that consumption of 1%/skim milk is more common among overweight/obese pre-schoolers, potentially reflecting the choice of parents to give overweight/obese children low-fat milk to drink. Across racial/ethnic and socioeconomic status subgroups, 1%/skim milk drinkers had higher BMI z-scores than 2%/whole milk drinkers. In multivariable analyses, increasing fat content in the type of milk consumed was inversely associated with BMI z-score. In longitudinal analysis, children drinking 1%/skim milk at both 2 and 4 years were more likely to become overweight/obese between these time points [16]. The goals of the current study were to use a nationally representative sample using the National Health and Nutrition Examination Survey (NHANES) to investigate the association between first milk fat content and weight status in early childhood and current milk fat content and weight status among children, adolescents, and young adults.

Both first and current milk fat content were associated with weight status. Children aged 2–6 years of age who had class I obesity were less likely to have been weaned to
whole milk. Among those 2–20 years old, individuals with overweight or obesity were less likely to consume whole milk and more likely to consume milk with lower fat content compared with those with a healthy weight. The findings are surprising and may indicate that the consumption of low-fat milk may actually contribute to overweight and obesity, contradicting the rationale for American Academy of Pediatrics (AAP) and American Heart Association (AHA) recommendations regarding the consumption
of reduced fat milk for obesity prevention. Prior longitudinal research indicates that high protein, low-fat intake in early childhood may lead to higher BMI. First milk content after weaning may be important in obesity prevention because early dietary practices influence subsequent dietary practices into adulthood [17, 18].

The mechanisms by which milk fat consumption may be protective against obesity may be explained by the fact that milk fat is one of the few food sources of butyric acid which has anti-inflammatory [19] effects, improves insulin sensitivity, and increases energy expenditure shown in mice models [20]. Thus, a possibility is that specific molecular properties of dairy fat are protective against obesity and metabolic dysfunction. Furthermore, full-fat milk may have increased satiety for children in comparison
with lower fat options [21].

The study strengths are the use of a nationally representative sample with measured height and weight data. However, the study has a number of limitations that include the lack of data regarding other aspects of the child’s diet beyond milk, which can contribute to child weight status. Also, as NHANES relies on self-reported parental data, it may not be accurate for children attending day care or school and is vulnerable to recall bias and social desirability bias. Additionally, NHANES represents repeated cross-sectional data, limiting the ability to evaluate the causation.


Adherence to the Mediterranean diet in metabolically healthy and unhealthy overweight and obese European adolescents: The HELENA study

Comments: Children and adolescents with obesity may be metabolically healthy, when no metabolic comorbidities are identified; at the opposite, they may be metabolically unhealthy when they show any metabolic abnormality. The presence of metabolic complications of obesity may be related to the exposure to lifestyle risk factors. Within dietary behaviors, the current tendency is to consider dietary patterns, providing composite information on the quality of the diet. The Mediterranean dietary pattern is characterized by a high consumption of vegetables, fruits, nuts, cereals, legumes and olive oil, moderate consumption of dairy products and low consumption of meat and poultry, and it is considered one of the healthiest dietary patterns in the world.

For this reason, it is adequate to explore if it is associated with the presence of metabolic complications in children with obesity. In the current study, it was observed, in European adolescents, that the adherence to the Mediterranean dietary pattern was significantly higher in children with obesity but not metabolic abnormalities than in those having some metabolic complications related to obesity, but the difference was not significant after adjustment for cardiorespiratory fitness. In addition, those adolescents with obesity having a low adherence to the Mediterranean dietary pattern had a higher risk of having metabolic abnormalities. Therefore, it seems that adherence to the Mediterranean dietary pattern in children with obesity may be beneficial to avoid the development of metabolic complications of obesity, but cardiorespiratory fitness seems also to play a role in the metabolic disturbances.

In recent decades, it seems children are not adhering so much to the Mediterranean dietary pattern even in the Mediterranean region. A recent systematic review, including 58 observational or intervention studies in children aged 2–20 years showed that Mediterranean diet adherence widely varied within the Mediterranean countries, with also large differences among the European Mediterranean countries [22]. In addition, the majority of the included studies showed that Mediterranean diet adherence was directly associated with physical activity, potentially with diet quality and inversely with sedentary behaviors [22]. To assess Mediterranean diet adherence in children and adolescents, different indices are used; the most widely found is the KIDMED index, but more research is needed in order to assess the validity and reproducibility of the used indices in different contexts not only in the Mediterranean area, but also in other locations where Mediterranean-like dietary patterns are being considered. There is also a need for further cohort and intervention studies to provide clear evidence on the association between the adherence to the Mediterranean diet and the development of obesity and also to confirm the role of the Mediterranean diet to avoid the development of metabolic complications in children and adolescents with obesity.


Fast food intake and excess weight gain over a 1-year period among preschool-age children

Comments: The increased consumption of fast food combined with reduced physical activity, have led to high obesity rates among children. Fast food is more energy-dense, highin saturated fats, salt, and sugar which contribute to obesity and other common health issues associated with obesity such as hypertension. Previous research has shown that fast food intake is common among children and has suggested that there is an association between fast food consumption and children becoming overweight or obese [23–25]. But it has not been clear whether eating fast food independently contributes to excess weight gain at such a young age. To address the gap in the association between fast food consumption and childhood obesity in the young ages, the investigators of the current study followed a large cohort of pre-school age children (ages 3–5) and their families for 1 year. Parents reported their children’s fast food intake frequency in six online surveys that were completed at 2-month intervals. The researchers found that about 8% of children transitioned to a greater weight status over the 1-year period. The strengths of the study are the possibility to adjust for other factors such as diet quality, exercise, screen time, sleep habits, and sociodemographic status, that could possibly explain away this relationship. Findings from this research should be used to inform guidelines and policies that can reduce fast-food marketing exposure to children and help support parents who may
be struggling to adopt healthier eating behaviors for their kids.


Nutrition and Risk of Obesity-Related Comorbidities

Impact of macronutrient supplements for children born preterm or small for gestational age on developmental and metabolic outcomes: A systematic review and meta-analysis

Comments: Infants born preterm or small for gestational age are at increased risk of obesity when adults. During decades, it was considered that a high energy and protein intake during the first few weeks after birth was the optimal strategy to improve growth in the subsequent period. However, it is currently well known that rapid weight gain during the first months of life is considered the early risk factor (first 2 years of life), showing the strongest association with later obesity [6, 26] and that rapid growth is more common in children who are small for gestational age or preterm than in those having appropriate body weight for gestational age or born at term.

In the current study, the authors performed a systematic review to identify the published results from randomized trials on the effects of early macronutrient supplements
fed to preterm and small for gestational age infants on different outcomes, including obesity, after hospital discharge. Twenty-one randomized and one quasi-randomized trials were included if the goal was to increase macronutrient intake to improve growth or development of infants born small. Co-primary outcomes were evaluated in toddlers (<3 years), childhood (3–8 years), and adolescence (9–18 years). Only one trial [27] reported the incidence of obesity, but it was not possible to extract data about the number of individual children; in this study, fortification of mother’s milk after hospital discharge for very preterm infants did not significantly influence growth parameters at 1 year of age compared with unfortified mother’s milk. In term small for gestational age infants, the optimal growth trajectory in terms of reaching the best obesity-related outcomes may be fast catch-up growth to about the 30th percentile in the first several months, with modest catch-up growth thereafter, to be around the 50th percentile by 7 years [28]. More randomized clinical trials are needed in order to establish the optimal growth trajectories and the best nutritional strategies in the different subgroups of children according to their weight and gestational age at birth.


Effects of oily fish intake on cardiometabolic markers in healthy 8- to 9-y-old children: The FiSK Junior randomized trial

Comments: Fish consumption is considered a healthy contributor to the usual diets because it has been associated with a low risk of cardiovascular diseases in adults via the reduction of cardiovascular risk factors; however, results in children are scarce and inconsistent and few randomized clinical trials addressed the issue. The current study has investigated the effect of consuming around 300 g of oily fish per week on blood pressure and serum triacylglycerol concentrations, considered both as primary outcomes, in prepubertal children aged 8–9 years, when compared with a similar intake of poultry and considering the potential sex differences. For the intervention strategy, families were advised to prepare the study food for the child twice a week for dinner and at least 3 times per week for lunch, to be able to reach a total weekly consumption of around 300 g of fish or poultry. As food products, the fish group received farmed salmon fillets and the poultry group, different cuts of organic chicken. The family was asked to cook the study foods, substituting some of the fish, poultry, or meat usually consumed and to maintain the usual diet and physical activity
during the follow-up period. Consumption of oily fish reduced triacylglycerol concentrations by 10% and increased HDL cholesterol concentrations by 5%, being consistent with the inverse relation between triacylglycerol and HDL. The reduction in serum triacylglycerol was mainly seen in boys. Changes in both triacylglycerol and HDL cholesterol concentrations were modified in a dose-dependent manner. The intervention had no effect on blood pressure, heart rate variability or glucose homeostasis
and no adverse events were observed.

Observed changes in triacylglycerol and HDL cholesterol concentrations are similar to those previously observed in fish oil trials in children [29]. As the consumed fish was rich in n-3 long-chain polyunsaturated fatty acids, the suggested mechanism is the activation of transcription factors leading to enhanced β-oxidation and reduction in hepatic VLDL-triacylglycerol release [30]. However, as the intervention was made of fish and not fish oil, the contribution to the observed effect by other nutrients, like for
example, vitamin D, cannot be excluded. The usual recommendation of fish intake is two or more portions per week (200–350 g); however, few children consume such amount on a regular basis. Results of the current study support the existing recommendations. There are some concerns about fish consumption related to the presence of contaminants as methylmercury; however, there is evidence showing that the benefits of the consumption, at the recommended amounts, are superior to the risks related to the potential contaminants [31]. For these reasons, health promotion programs should emphasize consumption of oily fish given that the small effects observed in metabolic variables may be linked with larger effects on disease reduction in the long term.


Effect of vitamin D3 supplementation on vascular and metabolic health of vitamin D-deficient overweight and obese children: A randomized clinical trial

Comments: Along with the high prevalence of obesity and metabolic syndrome in pediatric patients, children and adolescents in the majority of countries are diagnosed with vitamin D deficiency. Among the non-calcemic effects of vitamin D, a significant role is played by its impact on the hormonal regulation of glucose metabolism and the synthesis of adipokines by fat tissue. Vitamin D has a modulatory effect on the expression of the genes responsible for secretion of leptin and adiponectin. In vitro, 25(OH)D metabolites inhibit chronic immune-mediated inflammation by suppressing the production of the proinflammatory cytokines (IL-1β, IL-6, and IL-8). Low vitamin D concentrations are associated with markers of subclinical arteriosclerosis, including arterial endothelial dysfunction, and increased arterial stiffness [32, 33] that are predictors of future cardiovascular events [34].

Obese children have a higher risk of vitamin D deficiency, systemic inflammation, and cardiometabolic risk factors [35]. There is no consensus as to why vitamin D levels are decreased in obese individuals. The first point of view is that adipose tissue absorbs the fat-soluble vitamin D. Another hypothesis explains the low 25(OH)D concentrations by the fact that obese people have a decreased exposure to sunlight and decreased endogenous synthesis of vitamin D. Other hypotheses claim that vitamin D metabolism and 25(OH)D synthesis are impaired as a result of hepatic steatosis developing in obesity, and that high levels of leptin and IL-6 impair 25(OH)D synthesis by affecting vitamin D receptors [36].

In this study, the researchers found that correction of vitamin D deficiency in overweight and obese children by means of vitamin D3 supplementation (1,000 or 2,000 IU/day vs. 600 IU/day) did not affect measures of arterial endothelial function or stiffness, lipid profile indices, or systemic inflammation. However, vitamin D supplementation resulted in reductions in blood pressure and fasting glucose concentrations and led to improvements in insulin sensitivity. The study strengths are the randomized, double-masked, controlled design including a large sample of overweight or obese children all of them with vitamin D deficiency (serum 25(OH)D <20 ng/mL), and the use of state-of-the-art tests of vascular health; and ascertainment of body composition with DXA. Limitations of the study are the relatively high rate of attrition (30%), the relatively low rate of compliance (73%), which could have impacted the consequent responsive changes in the outcome variables. Also, the fact that the majority of participants were black (93%), the results may be not applicable to other ethnicities or populations. We may also speculate that the relatively short duration of exposure to vitamin D supplementation (6 months) may impact the lack of effect on measures of arterial endothelial function or stiffness or systemic inflammation.
Despite the consensus with regard to the need to treat vitamin D insufficiency in obese patients, there is no common point of view on the dosage and duration of cholecalciferol administration appropriate for vitamin D supplementation. However, optimization of children’s vitamin D status may improve their cardiovascular health. Long-term follow-up of this cohort can be important to assess whether early intervention will result in later long-term potential benefits.


The role of genetic predisposition, programing during fetal life, family conditions, and post-natal diet in the development of pediatric fatty liver disease

Comments: NAFLD comprises a wide spectrum of diseases ranging from simple steatosis with fat accumulation to steatohepatitis, fibrosis, and even cirrhosis or hepatocellular carcinoma. NAFLD is estimated to affect 8–34% of overweight children and adolescents [37]. Despite intense research efforts, mechanisms underlying the onset and progression of the disease are still not fully understood. Therefore, the power of the current study is the evaluation of the independent role of different variables in the progression of NAFLD among children with obesity. The researchers assessed the impact of the genetic contribution through evaluation of the genetic predisposition by genotype checking of the I148 M patatin-like phospholipase domain-containing 3 (PNPLA3) that is strongly associated with the severity of steatosis and fibrosis and the presence of non-alcoholic steatohepatitis. They also performed an assessment of prenatal factors (pregnancy, intrauterine development, gestational age, and birth weight), type of feedings (early type, breastfeeding or not, and later feeding, with fructose consumption as indicator), family history and socioeconomic factors, metabolic parameters, and the contribution of circulating vitamin D status. Their final logistic model, with steatohepatitis and/or fibrosis as outcome variables, indicates genetics with family history, birth weight, dietary indicators (not being breastfed and daily fructose consumption later on), and a poor vitamin D status as predisposing factors, whereas higher level of maternal occupation (SES indicator) stands as an independent protective factor. In the final cumulative analysis, those with the worst condition in these variables have approximately 30% higher risk of developing fibrosis and/or more complicated liver disease from NAFLD.

The study strengths are the inclusion of a large number of patients, that their diagnosis of fatty liver staging was based on biopsy results (which is the gold standard for
diagnosis), the selection of a naïve cohort with absence of specific dietary or other therapeutic treatment, the availability of complete familial, maternal, and neonatal data, and also the evaluation of the genetic predisposition by genotype. The limitations of the study include its cross-sectional and retrospective design. Therefore, it cannot determine causation, only associations. However, since genetic predisposition cannot be modified, the findings call for further studies to investigate the possibility of multistep interventions to prevent unfavorable health outcomes, as recommendations of breastfeeding and keeping balanced dietary habits from an early age (reduction of fructose in the diet and supplementation with vitamin D in those with vitamin D deficiency, etc.).


Effects of a carbohydrate-restricted diet on hepatic lipid content in adolescents with non-alcoholic fatty liver disease: A pilot, randomized trial

Comments: The pathogenesis of NAFLD in children is not fully understood but is thought to involve complex interactions between alterations in nutrient metabolism, insulin resistance, and the onset of inflammation in multiple organ systems [38]. While the principal existing therapies target the metabolic disorders associated with fatty liver, no treatment currently exists to directly reverse hepatic fat infiltration [39]. Although it is clear that glucose has important effects on obesity and other adverse health responses, it appears that fructose, when consumed at high levels, has additional adverse effects on increased liver fat, visceral fat, muscle fat, and triglycerides [40, 41].

A previous study [42] showed that overweight children with early signs of NAFLD had a significantly higher mean daily total energy intake when compared to overweight children without NAFLD (∼250 kcal/day), which mainly seemed to result from a higher daily total fructose and total glucose intake originating from a markedly higher soft
drink and juice intake. The same study reported that both bacterial endotoxin and lipopolysaccharide-binding protein levels were significantly higher in overweight children with NAFLD than in those without, suggesting that alterations of intestinal barrier function and, subsequently, an increased translocation of bacterial endotoxin
are critical in the development of NAFLD.

Evidence from studies in adults have shown that reducing intake of carbohydrate sources such as added sugars, high glycemic grains, and fructose may be the most effective approach to reverse fatty liver by significantly reducing hepatic de novo lipogenesis (DNL) [43]. Limiting hepatic DNL would reduce the accrual of hepatic lipids
and simultaneously enhance their disposal via mitochondrial β-oxidation. A previous small pilot interventional study in overweight children with NAFLD [42] suggests that targeting fructose intake even with moderate measures may be beneficial for overall health status of overweight children with NAFLD.

The data of the current study reinforce the previous findings and suggest that recommendation of a moderately carbohydrate-restricted diet (CRD) to obese adolescents
with NAFLD results in favorable changes in body composition, depletion of liver fat, and improvement in glucose metabolism, with more favorable outcomes compared to a fat-restricted diet (FRD), even in the absence of intentional caloric restriction. Although hepatic lipid was decreased with the CRD in the present study, the change was not greater than that observed with the FRD. The CRD group had greater decrease in insulin resistance than the FRD group. Moreover, the CRD group tended to lose more weight, and lost greater fat mass, than the FRD group, making it difficult to isolate an independent contribution of diet composition. Thus, it is not clear whether CRD has effects on hepatic lipid that are independent of weight loss. The study is limited by the small number of participants included in the final analysis (n = 25) and the use of self-reported dietary intake using food records that may result in underreporting and not accurately reflect actual intake. Also, the short duration of the study prevents from determining the durability of the dietary intervention in reversing NAFLD long term. However, since depleting liver fat may be critical for reducing the risk of disease progression and risk of other metabolic diseases, we can conclude that larger studies are needed to determine whether a CRD induces change in hepatic lipid independent of the change in body fat.