children

Review
Micronutrient Deficiency in Children and Adolescents with
Obesity—A Narrative Review
Valeria Calcaterra 1,2,† , Elvira Verduci 2,3, *,† , Chiara Milanta 2 , Marta Agostinelli 2 , Carolina Federica Todisco 2 ,
Federica Bona 2 , Jonabel Dolor 2 , Alice La Mendola 2 , Martina Tosi 2 and Gianvincenzo Zuccotti 2,4

1 Pediatrics and Adolescentology Unit, Department of Internal Medicine, University of Pavia, 27100 Pavia, Italy
2 Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy
3 Department of Health Sciences, University of Milan, 20142 Milan, Italy
4 Department of Biomedical and Clinical Science, University of Milan, 20157 Milan, Italy
* Correspondence: [email protected]
† These authors contributed equally to this work.

Abstract: Childhood obesity represents a serious public health burden. Despite excessive dietary
consumption, children with obesity present high rates of micronutrient deficiencies, such as defi-
ciencies in minerals and specific vitamins; micronutrient deficiencies may have a pathogenic role in
obesity-related metabolic comorbidities. In this narrative review, we analyzed the main deficiencies
associated with obesity, their clinical consequences, and the evidence about a possible supplemen-
tation. Iron; vitamins A, B, C, D, and E; folic acid; zinc; and copper deficiencies represent the most
common deficient microelements. The relationship between obesity and multiple micronutrient
deficiencies remains unclear, and different mechanisms have been proposed. The medical care plan
for pediatric obesity should include food choices with high nutritional content as part of a crucial
approach to obesity-related complications. Unfortunately, only a few studies are available regarding
the efficacy of oral supplementation or weight loss for treating them; thus, continuous nutritional
monitoring is necessary.

Citation: Calcaterra, V.; Verduci, E.;

Keywords: pediatric obesity; micronutrients; children; deficiency; malnutrition
Milanta, C.; Agostinelli, M.; Todisco,
C.F.; Bona, F.; Dolor, J.; La Mendola,
A.; Tosi, M.; Zuccotti, G.
Micronutrient Deficiency in Children
and Adolescents with Obesity—A 1. Introduction
Narrative Review. Children 2023, 10, Childhood obesity has become a global epidemic and a serious public health burden;
695. https://doi.org/10.3390/ “globesity” is a new neologism that clearly describes this high-prevalence risk worldwide [1,2].
children10040695 Indeed, the prevalence of worldwide obesity has nearly tripled from 1975 to 2016 in children
Academic Editor: George and adolescents aged 5–19 years, from just 4% to 18%, respectively, reaching over 340 million
Antonogeorgos children with obesity or overweight in this age group, similarly among both boys and girls [3].
Moreover, according to estimates by the World Health Organization (WHO), 39 million
Received: 6 March 2023 children younger than 5 years were obese or overweight in 2020, and the fact that obesity
Revised: 26 March 2023
affects children as young as 2 years old is even more concerning [1]. A further increase in
Accepted: 4 April 2023
pediatric obesity has been associated with the recent COVID-19 pandemic [4,5]. If current
Published: 7 April 2023
trends continue, obesity is expected to affect 60% of adult men, 50% of adult women, and
25% of children by 2050 [1]. Prevailing evidence suggests that the rate of youth obesity has
continued to increase, especially among children and adolescents with parental obesity [6].
Copyright: © 2023 by the authors.
Pediatric obesity is a crucial risk factor for adverse nutritional complications. The
Licensee MDPI, Basel, Switzerland. nutritional status of children and adolescents with obesity seems to be a paradoxical
This article is an open access article malnutrition. In fact, despite excessive dietary consumption, children with obesity present
distributed under the terms and high rates of micronutrient deficiencies, such as deficiencies in minerals and specific
conditions of the Creative Commons vitamins; micronutrient deficiencies may have a pathogenic role in obesity-related metabolic
Attribution (CC BY) license (https:// comorbidities [7–12].
creativecommons.org/licenses/by/ In this narrative review [13], we analyzed and summarized the main deficiencies
4.0/). associated with obesity, their clinical consequences, and the evidence about a possible

Children 2023, 10, 695. https://doi.org/10.3390/children10040695 https://www.mdpi.com/journal/children

Children 2023, 10, 695 2 of 16

supplementation. The medical care plan for pediatric obesity should include food choices
with high nutritional content as part of a crucial approach to obesity-related complications.

2. Methods
An analysis of the available literature and a non-systematic summation on the topic
of micronutrient deficiency in children and adolescents with obesity were proposed [13].
English-language relevant literature from the past 15 years was considered, including
original papers, meta-analyses, clinical trials, and reviews. Letters, case reports, or series
were not included. The abstracts of the literature were assessed (n = 128), and the full
texts of potentially relevant articles (n = 45) were reviewed and analyzed by the authors.
The reference list of all articles was also checked to identify relevant papers. The research
terms adopted, alone and/or combined, were obesity, adolescents, children, micronutrient
deficiency, trace element deficiency, mineral deficiency, deficiencies diagnosis, oral supple-
mentation, nutritional intervention, iron, anemia, inflammatory anemia, vitamin A, vitamin
C, vitamin D, vitamin E, vitamin B12, folic acid, zinc, and copper. The databases PubMed,
Scopus, and Web of Science were used for the literature research. The contributions were
independently collected by C.M., A.M., F.B., C.F.T., and J.D., and critically discussed and
analyzed with V.C. and E.V. The resulting draft was critically revised by V.C., E.V., and G.Z.
The final version was approved by all.

3. Childhood Obesity
Obesity is a pathological condition characterized by excessive adipose tissue storage
as a consequence of an energy imbalance between caloric intake and expenditure [14].
The weight-to-length ratio is used to diagnose overweight and obesity in children up
to 24 months old, using the WHO 2006 reference curves. After the age of 2 years, it is based
on the body mass index (BMI), using the WHO 2006 reference system up to 5 years and the
WHO 2007 reference system thereafter [15] (Table 1).

Table 1. Obesity and overweight diagnostic criteria in children.

Age
0–2 years 2–5 years 5–18 years
Index Weight-to-lenght ratio Body mass index Body mass index
Reference WHO 2006 WHO 2006 WHO 2007
>85th percentile * Overweight risk Overweight risk Overweight
>97th percentile * Overweight Overweight Obesity
>99th percentile * Obesity Obesity Severe obesity
* The 85th, 97th, and 99th percentiles’ approximate z-scores of +1, +2, and +3, respectively. WHO—World
Health Organization.

The underlying etiology of obesity is extremely complex and has been the subject
of extensive research [1]. Childhood obesity is the result of a complex interaction among
several risk factors involving genetic, environmental, nutritional, and socio-economic
influences [15]. Although the pathophysiology of obesity remains controversial, the energy
imbalance between consumed and expended calories is considered one of the main drivers
of the development of obesity and overweight [16,17]. The WHO attributes the increased
prevalence of childhood obesity to a global shift in diets towards energy-dense, nutrient-
poor foods and increased use of sugar-sweetened beverages that greatly impact the risk
of obesity due to high caloric intake [1]. These changes have also been accompanied by
factors predisposing to chronic low energy expenditure, such as less physical activity due
to increasingly sedentary lifestyles [15]. However, there are also socio-economic factors [18]
as well as developmental factors such as genetic and epigenetic conditions that predispose
to the risk of obesity [19].
The inflammation induced by obesity and associated behaviors can cause many corre-
lated diseases [20]. Complications of obesity can occur in both the short and long term. As
 the risk of obesity due to high caloric intake [1]. These changes have also been
accompanied by factors predisposing to chronic low energy expenditure, such as less
physical activity due to increasingly sedentary lifestyles [15]. However, there are also
socio-economic factors [18] as well as developmental factors such as genetic and
Children 2023, 10, 695 epigenetic conditions that predispose to the risk of obesity [19]. 3 of 16
The inflammation induced by obesity and associated behaviors can cause many
correlated diseases [20]. Complications of obesity can occur in both the short and long
term. As the prevalence and severity of pediatric obesity increases, these changes are also
the prevalence and severity of pediatric obesity increases, these changes are also beginning
beginning to be seen in children [21–23]. Obesity is associated with an increased risk of
to be seen in children [21–23]. Obesity is associated with an increased risk of serious health
serious health conditions including cardiovascular disease, high blood
conditions including cardiovascular disease, high blood pressure/hypertension, renal co-
pressure/hypertension, renal comorbidities, gastrointestinal disease such as non-alcoholic
morbidities, gastrointestinal disease such as non-alcoholic fatty liver disease, non-alcoholic
fatty liver disease, non-alcoholic steatohepatitis, cholelithiasis, hepatocellular carcinoma,
steatohepatitis, cholelithiasis, hepatocellular carcinoma, pulmonary disease such as asthma,
pulmonary disease such as asthma, and obstructive sleep apnea. Obesity is also related to
and
endocrine and sleep
obstructive apnea.
metabolic Obesity such
disorders is alsoasrelated to endocrine
dyslipidemia, and metabolic disorders
hyperandrogenemia, early
such as dyslipidemia,
pubertal development, hyperandrogenemia,
polycystic ovarianearly pubertal
syndrome development,
(PCOS), polycystic
hyperglycemia, ovarian
insulin
syndrome
resistance that can evolve into prediabetes and subsequently into type-2 diabetes mellitus,and
(PCOS), hyperglycemia, insulin resistance that can evolve into prediabetes
subsequently into type-2
and musculoskeletal diabetes mellitus,
comorbidities and and
such as foot musculoskeletal comorbidities
lower limb pain suchmain
[2,4,15,24]. The as foot
and lower limb pain [2,4,15,24]. The main
possible complications of obesity are illustrated.possible complications of obesity are illustrated.
Moreover,
Moreover,obesity
obesityis also often
is also related
often to psychosocial
related complications;
to psychosocial indeed,
complications; children
indeed,
with obesity are more likely to experience low self-esteem, develop depression,
children with obesity are more likely to experience low self-esteem, develop depression, have a
reduced quality of life, and experience social isolation during adolescence
have a reduced quality of life, and experience social isolation during adolescence [8,9]. [8,9].
All
Allthese
thesecomorbidities contributeto
comorbidities contribute toincreased
increasedmorbidity
morbidityandand mortality
mortality in adulthood
in adulthood
associated
associatedwith
withbeing
being inin the
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obesityininpediatric
pediatricage
age[6–29],
[6–29], Figure
Figure 1. 1.

Figure1.1.Comorbidities
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Since
Sinceobesity
obesity involves importantcomorbidities
involves important comorbiditiesboth
both physically
physically and
and psychologically,
psychologically,
timely
timelytreatment
treatmentof of
children andand
children adolescents withwith
adolescents overweight/obesity is extremely
overweight/obesity impor-
is extremely
tant. The treatment approach for childhood obesity should be broad, sequential, dynamic,
and multidisciplinary [24,29,30].
Non-pharmacological preventive approaches and therapies are the most important
treatments for childhood obesity. Firstly, breastfeeding is the primary prevention for over-
weight and obesity; a few studies reported a significative risk reduction (26%) of developing
obesity later in life in breastfed children compared to those who received formula [24,31].
Additionally, an interesting systematic meta-analysis confirmed the protective role of
breastfeeding, describing a risk reduction of 15% [32].
The fundamental pillars of non-pharmacological treatment are lifestyle changes such
as education, healthy eating, and physical activity [12,13,24].
Children 2023, 10, 695 4 of 16

Indeed, families are educated about lifestyle changes, such as the reduction of sugar
and animal origin fat consumption and the increase of vegetable and fruit consumption,
before beginning a personalized diet [15,23,24,31]. Furthermore, it is recommended that
there is moderate daily physical activity between 30 and 60 min [15,24,30,33]. Moreover, it
is of key importance to assure adequate sleep hygiene and duration since sleep deprivation
represents a risk factor for obesity development [15]. Lastly, it must be investigated
whether there is discrimination and bullying to prevent or cure social problems that could
be associated with obesity [14].
Pharmacotherapy for weight loss in pediatrics is debated and represents a second-line
approach. Actually, a limited number of anti-obesity medications have been approved for
the pediatric population compared to adults. Pharmacological treatment is considered for
subjects with severe obesity older than 10 years of age who have not responded to 1-year
nutritional and lifestyle treatments, as well as for those with multisystem comorbidities [29].
Despite their therapeutic efficacy, drugs currently used for weight loss have many
limitations because of their high incidence of side effects (between 3% and 44% depending
on the drug used and different studies), prohibitive costs, and unpopularity due to historical
problems associated with their use [34].
Surgical treatment is reserved for cases of resistance to weight loss and control of
comorbidities after lifestyle changes and/or pharmacological treatment [15,24,30,33].

4. Micronutrients Deficiency in Childhood Obesity

Childhood obesity is an important risk factor for different adverse nutritional condi-
tions. Among these, it should be considered also trace element deficiencies. Indeed, specific
features of obesity or the bad habits typically associated with it can lead to deficiencies in
different trace elements.

4.1. Iron Deficiency

Little evidence is available regarding the association between pediatric obesity and
trace element deficiency, although obesity and iron deficiency in particular are two of the
most common malnutrition conditions in the world [35]. Two recent meta-analyses demon-
strated an association between childhood obesity and increased risk of iron deficiency: the
first one involved only patients under the age of ten years [36], while the more recent and
second one confirmed the presence of this association even in older patients [37].
Different assumptions can be made to explain this association. First of all, iron defi-
ciency can be caused by poorer iron nutritional intake due to unhealthy eating habits (junk
food, low fruit and vegetable consumption, and more processed food consumption) [37].
However, this hypothesis does not completely explain iron deficiency: indeed, few studies
regarding iron deficiency in childhood obesity also included analysis of nutrient intake,
and the association between the two conditions was confirmed even when including diet
intake as a covariate [8,38].
Other mechanisms explaining iron deficiency in obesity are not fully understood. It is
hypothesized that it can be due to increased iron requirements for elevated blood volume
consequent to adipose tissue [39].
Furthermore, increased inflammation may contribute to iron deficiency by reducing
iron absorption [39–41]. Indeed, obesity is linked to a state of persistent low-grade inflam-
mation because of metabolic problems brought on by cells’ increased exposure to fatty
acids [42]. Free fatty acids usually accumulate in ectopic places when the storage capacity
of adipose tissue is exceeded by the amount of fatty acids present, and this exposure may
cause cell malfunction, cell death, and inflammation [43].
Iron shortage and inflammation are related, since Hepcidin, which has a role both as
a homeostatic regulator of systemic iron metabolism and as a mediator of host defense
and inflammation, is required for its regulation [44–46]. Hepcidin is produced by the liver,
which represents the primary site for its secretion in response to the detection of levels of
Children 2023, 10, 695 5 of 16

both circulating iron and iron stores [46,47]. It prevents the intestinal absorption of iron
and binds to ferroportin-1, promoting its internalization and degradation [47].
Proinflammatory cytokines, including interleukin (IL)-6, bone morphogenetic proteins,
and iron overload increase the hepatic synthesis of Hepcidin. On the other hand, iron
insufficiency, hypoxia, and inefficient erythropoiesis downregulate its production [48]. For
this reason, inflammatory anemia, which is defined by decreased iron levels in the blood and
increased cellular iron reserves, is associated with higher levels of hepcidin [49]. Therefore,
it is reasonable to assume that the chronic low-grade inflammation associated with obesity
can produce inflammatory cytokines, leading to the release of hepatic Hepcidin [40].
To further support this hypothesis, a study reported that overweight children had
higher circulating Hepcidin and poorer iron status when compared to normal-weight chil-
dren, despite similar dietary iron intake [50]. In conclusion, low-grade inflammation typical
of the obesity condition causes an increased release of Hepcidine by the liver. Hepcidine
binds to ferroportine expressed by different tissues, resulting in its internalization in the cell
and degradation in the lysosome. This is especially significant for the duodenal mucosa,
where iron is absorbed, and for macrophage cells, which are appointed to recycle iron from
senescent or damaged erythrocytes [51]. Moreover, a small fraction of intracellular iron
is maintained in the labile iron pool in the cell cytosol, while the majority is utilized in
enzymes or sequestered in ferritin to prevent iron-mediated oxidative damage. Ferritin
Children 2023, 10, x FOR PEER REVIEW 6 of 17
is upregulated by inflammation, with consequent increased iron stores in the cells [52].
Effects of inflammation on iron metabolism are shown in Figure 2.

Figure 2.
Figure Inflammationeffect
2. Inflammation effectonon iron
iron metabolism
metabolism (created
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Lastly,that
Given the synthesis
low-gradeand secretion ofisHepcidin
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find indi-
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more clearly define
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The tissue in for
gold standard systemic
iden-
Hepcidin
tifying ironlevels [53]. and iron deficiency anemia is still a bone marrow test, but it is a
deficiency
Two separate
painful, intrusive, and research studies
expensive found [58].
procedure that Serum
oral iron supplementation
iron, therapy
serum ferritin, soluble was
trans-
ineffective at replenishing iron stores in children with obesity. This provided
ferrin receptor, and transferrin saturation are common biomarkers of iron status that can additional
evidence
be useful on for the
the crucial roleofofanemia
diagnosis inflammation in iron
[59]. When deficiency
there is anemia,in childhood
serum ironobesity.
levels are Ac-
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always to both
Thestudies’
serum findings, bloodwhich
ferritin level, Hepcidin was linked
is indicated by to hypoferremia
a level and30
of less than a worse
g per
liter, is the most sensitive and specific test used to detect iron deficiency. The strongest
predictor is a ferritin level of less than 100 g/L, and a substantially higher cutoff ferritin
level should be used to establish iron-deficiency anemia accompanied by inflammation.
Less than 16% transferrin saturation levels signify an inadequate iron supply to maintain
Children 2023, 10, 695 6 of 16

outcome from oral iron therapy [54,55]. On the other hand, two studies showed that weight
loss was linked to improved iron and inflammatory status in several groups of obese
children [56,57].
Given that low-grade inflammation is a hallmark of obesity, it is critical to find in-
dicators that may distinguish anemia caused by chronic disease from anemia due to an
iron shortage in a patient with a chronic condition such as obesity. The gold standard for
identifying iron deficiency and iron deficiency anemia is still a bone marrow test, but it
is a painful, intrusive, and expensive procedure [58]. Serum iron, serum ferritin, soluble
transferrin receptor, and transferrin saturation are common biomarkers of iron status that
can be useful for the diagnosis of anemia [59]. When there is anemia, serum iron levels
are always low. The serum ferritin level, which is indicated by a level of less than 30 g per
liter, is the most sensitive and specific test used to detect iron deficiency. The strongest
predictor is a ferritin level of less than 100 g/L, and a substantially higher cutoff ferritin
level should be used to establish iron-deficiency anemia accompanied by inflammation.
Less than 16% transferrin saturation levels signify an inadequate iron supply to maintain
normal erythropoiesis [60]. Increased serum levels of the soluble transferrin receptor (s-TfR)
are suspected in an iron deficiency condition [61]. Hepcidin levels can currently not be
accurately measured [60]. In Table 2, the most important laboratory findings in different
kinds of anemia are summarized.

Table 2. Differential diagnosis of anemia.

Iron Deficiency Anemia Chronic Disease Anemia Iron Deficiency Anemia in Chronic Disease
Serum Iron Decreased Decreased Decreased
Ferritin Decreased Increased Often Increased
s-TfR Increased Decreased Increased
s-TfR—Soluble Transferrin Receptor.

Another possibility for a correct diagnosis to avoid mistakes due to inflammation or

aging is to evaluate a complete blood count with reticulocyte hemoglobin content (CHr).
Reticulocytes are markers of iron availability in iron-deficient erythropoiesis [59].
It is very important to identify and treat iron deficiency in children because of its
consequences in pediatrics. Indeed, it has been demonstrated that iron deficiency has a
negative effect on motor skills, cognition, and behavior that can persist in the long term [62].

4.2. Vitamins A, C, and E Deficiency

Children and adolescents with obesity have been found to have a higher risk of low
vitamin A, vitamin E, and vitamin C concentrations than children and adolescents with
normal weight [9,63]. Vitamins A, C, and E in particular have been demonstrated to be
related to leptin concentration [64,65].
Low vitamin C concentration was linked to greater body fat, abdominal fat, and
waist/height ratio, according to research by Garcia and colleagues on 197 Mexican chil-
dren [64]. By a variety of different methods, including control of adipocyte lipolysis [66],
an inflammatory response [67], and suppression of leptin levels [68], vitamin C may reduce
adiposity. Although there are not many studies on the effectiveness of vitamin C supple-
mentation, some data suggests that it may lower leptin levels in the blood and reduce body
weight and adiposity in rats [69].
Similar to this, it was shown that vitamin E concentrations were negatively correlated
with all obesity-related indicators [64]. These findings are in line with earlier research that
linked obesity and reduced vitamin E concentrations [9,70]. As suggested in the animal
model, vitamin E may play a function in leptin metabolism, which could account for this
connection [71]. Lastly, vitamin A concentration was discovered to be favorably correlated
with indices of obesity by Garcia and colleagues [64]. These findings were in stark contrast
to earlier research that did not focus on children but indicated an inverse relationship
between vitamin A concentration and weight, BMI, and hip circumference [72,73]. The
Children 2023, 10, 695 7 of 16

association between vitamin A and adiposity may be different in those with a greater BMI
and body fat content since the action of vitamin A on adipogenesis, specifically retinoic
acid, appears to be dose-dependent [74].
Moreover, triglyceride and total cholesterol concentrations are positively correlated
with vitamin A and E concentrations [64]. This might be a result of how vitamins A and E
affect lipid metabolism. In more detail, the retinaldehyde dehydrogenase 1 enzyme helps
vitamin A regulate lipid metabolism [75]. In order to avoid oxidative damage and preserve
lipids from oxidation, vitamin E is important [76].
Regarding the supplementation of vitamin A in teenagers, no systematic reviews are
available. Only a small number of studies on teenagers from Bangladesh [77], Kenya [78],
and Indonesia [79] examined the effects of vitamin A supplementation, which significantly
reduced anemia, but it is not clearly described how it affects body composition.

4.3. Vitamin B Deficiency

During childhood and adolescence, it is critical to maintain adequate folate and
cobalamin status for cellular processes, notably nucleic acid synthesis, cell division,
homeostasis of both amino acids and lipids, red blood cell formation, and nervous
system myelination [80,81].
Their deficiency has been linked to several risks, such as failure to thrive, delayed
psychomotor development, megaloblastic anemia [82,83], and, recently, poor event-free
survival in cancer [84]. Moreover, low levels can cause DNA synthesis interference, cellular
inflammation, elevated synthesis of fat, and hyperhomocysteinemia, an independent risk
factor for insulin resistance and cardiovascular disease [85,86].
Studies on optimal serum concentrations in healthy European children are still scarce,
and no universally accepted cut-offs have been established [87].
However, several studies have assessed that children with malnutrition related to over-
weight, obesity, and metabolic syndrome are at increased risk of mineral and vitamin defi-
ciencies [88,89]. Hence, reduced vitamin B12 and folate serum levels may be caused by poor
dietary content; short-term, repeated restricted diets; or increased requirements [11,89].
In a prospective and descriptive study, Hamiel et al. [9] demonstrated that Israeli
children and adolescents with obesity (aged 6 to 19 years) had significantly lower vitamin
B12 concentrations when compared to those with normal weight, and that 10% of children
with obesity had low serum B12 concentrations. Obesity was associated with a greater than
4-fold risk for low cobalamin levels, and for each unit increase in BMI-standard deviation
scores (SDS), there was a 24% increased risk of low serum cobalamin concentrations [11].
Additionally, in a randomized controlled trial conducted on adolescents with obesity
(mean age of 13.4 years) with pre-diabetes and/or a clinical feature of insulin resistance,
vitamin B12 status was found below or borderline in almost one-third of them [90].
Gunanti et al. also showed that vitamin B12 serum concentrations and folate levels in
Mexican children (aged 8–15 years) were inversely associated with BMI and that higher
serum concentrations of vitamin B12 were associated with a reduced obesity risk [91].
Accordingly, a recent prospective, longitudinal cohort study, based on a population
aged between 2 months and 18 years, reported an inverse correlation between BMI-SDS
with respect to both folate and cobalamin; the correlation between cobalamin, but not folate,
and BMI-SDS strengthened with increasing age [87].
Healthy eating habits should be promoted to prevent obesity and its complications.
Moreover, dietary treatment of children with obesity should focus not only on reducing
dietary calories but also on choosing high-nutrient density foods [92].
Preclinical and clinical studies in rats and adults, respectively, showed that vitamin
B12 and folic acid supplementation could reduce the risk of developing cardiac and cerebral
vascular disease and may have positive effects on anthropometric and metabolic biomarkers
of obesity, such as triglyceride, HDL-C, and insulin serum levels, HOMA-IR, and waist-to-
hip ratio [86].
Children 2023, 10, 695 8 of 16

To date, a randomized, double-blind, placebo-controlled trial has shown that folic

acid supplementation could reduce plasma homocysteine (tHcy) in children with obesity,
especially in males and those with low serum folate levels [93]. Moreover, Peña et al.
demonstrated that. Folic acid supplementation improved endothelial function in children
with type 1 diabetes, increased folate status, and reduced tHcy in children with obesity
without diabetes [94].

4.4. Vitamin D Deficiency

Vitamin D has many crucial roles in the human body: it is very important for cal-
cium and phosphorus metabolism in the bone system, for immune functions, and some
researchers found that it decreases the risk of chronic illnesses [95].
During the last few decades, a lot of studies were able to underline the prevalence of
vitamin D deficiency in childhood and they found a significant association between childhood
overweight and obesity with vitamin D deficiency (25-OH vitamin D < 20 ng/dL).
Turer et al. designed a cross-sectional study in the USA in which 12,292 children aged
6–18 years were included. This is one of the first studies that aimed to evaluate the vitamin
D deficiency rate in children with obesity in the USA. It showed a significantly higher
prevalence of vitamin D deficiency among children with overweight and obesity compared
to those with healthy weight control, and severe obesity appeared to be particularly at
risk; in fact, one in two children with severe obesity were vitamin D deficient, even after
adjustments for cofounding factors [96]. Subsequent meta-analyses later confirmed vitamin
D deficiency as a condition associated with obesity in young people [97,98].
The most likely explanation of this association appears to be the sequestration of
fat-soluble vitamin D within the enlarged adipose mass in people with obesity [99,100].
Wortsman et al., in fact, highlighted that obesity does not affect the skin’s capacity to
produce vitamin D3, but instead it may alter the vitamin D3 release from the skin into
the circulation because of a more sequestered rate of cutaneously synthesized vitamin D3
by subcutaneous fat [99]. Leptin, which is overrepresented in populations with obesity,
could also be responsible for this association. There is evidence in populations with obesity
that leptin appears to activate a pathway that inhibits the renal enzyme responsible for the
active form of vitamin D production [101]. In addition, obesity is mostly associated with a
more sedentary lifestyle, usually associated with less sun exposure, and this association can
also explain why children with obesity have lower circulating levels of vitamin D [10,102].
Eventually, except in some populations where fish, fish oil, and fish eggs are frequently
consumed, children with obesity have even lower intakes of vitamin D, subsequently
resulting from poor quality diets.
Some studies have investigated a possible association between ethnicity and vitamin D
deficiency. Accordingly, the prevalence of vitamin D deficiency was significantly higher in
Afro-American children with obesity compared with Caucasian subjects [96,102]. However,
it is known that Afro-American individuals do have a reduced skin synthesis of vitamin D
due to their darker skin pigmentation [103], and this association may also be attributable to
the high rates of obesity in black children [104,105].
In the current literature, certain studies aim to assess whether there are differences
in circulating vitamin D levels following oral supplementation in patients with obesity
compared with control patients. In Wortsman et al.’s study, it was found that oral vitamin
D supplementation at higher doses in the population with obesity is still required [99]. In
this line, Harel et al.’s study also suggests higher doses of administration in those children
with obesity who do not normalize their vitamin D circulating level after the initial course
of treatment [10]. This is important because several studies have described the beneficial
effects of vitamin D supplementation in the treatment of MetS-related diseases, such as lipid
profile, insulin resistance and hyperglycemia, hypertension, and obesity [106,107]. There
is limited evidence in children, and study results are quite controversial. A recent meta-
analysis, which included eleven randomized-control trials based on an adult population,
demonstrated that vitamin D supplementation could contribute to reduced BMI and waist
Children 2023, 10, 695 9 of 16

circumference but not to weight loss [108]. On the contrary, individuals aged 6–14 years
showed no significant effects of vitamin D supplementation on BMI, waist circumference,
waist-to-hip ratio, and percentage of fat tissue [109–111].
An adequate vitamin D status is important during the entire pediatric age, above all to
guarantee bone health and avoid nutritional rickets, but it is seen that its supplementation
could be useful in children with obesity too. However, to date, population-wide vitamin D
deficiency screening in healthy individuals is not recommended, and 25(OH)D evaluation
should be reserved for subjects at vitamin D deficiency risk [112].

4.5. Zinc and Copper Deficiency

Micronutrient deficiencies are extremely widespread all over the world and have
many consequences for public health [113]. Metallic elements have fundamental biological
functions; their deficiencies may cause different diseases and disorders [12] and may be
related to obesity and overweight [7].
Multiple studies have shown that trace element levels could be deficient in children
with obesity [114]. Despite that, the relationship between serum copper (Cu) and zinc
(Zn) concentrations and overweight/obesity is still controversial and needs to be fur-
ther investigated. Zn is an essential micronutrient with an important biological role: it
contributes to metabolic and endocrine regulation, immune response, and multiple bio-
chemical reactions [12]. Cu plays an important role in preventing superoxide damage with
its function in copper/zinc superoxide dismutase (Cu/Zn SOD), which helps to reduce
the obesity risk [115]. Controversially, an excessive level of serum Cu can damage the
oxidant/antioxidant system, causing an increase in reactive oxygen species (ROS) and
reactive nitrogen species (RNS) in the organism [116].
Cu level disorders may also affect Zn metabolism, leading to an increase in oxidative
stress and the inflammatory response, both of which seem to have a key role in obesity
pathogenesis [116]. Several studies have analyzed the relationship between serum Cu
and overweight/obesity; some of those found a significantly higher serum Cu level in
children with obesity than in healthy controls [12,114,117–119], whilst others observed no
relationship [120,121]. Interestingly, Lima et al. [117] reported a higher concentration of
serum Cu in individuals with obesity but no difference in Cu erythrocyte concentration
between children with obesity and healthy weight controls. Gu et al. [115] reported that
the serum Cu level was higher in children and adults with obesity without any significant
difference in serum Cu between the overweight and control groups of both populations.
Their results suggest that a higher serum Cu concentration might be associated with an
increased obesity risk [115]. Jacksic et al. [120] observed a strongly positive correlation be-
tween serum Cu level and C-reactive protein, which means that there may be an association
between childhood obesity and oxidative stress and inflammation, even if no relationship
between Cu and Zn concentrations and obesity was found.
On the other hand, certain studies analyzed the relationship between serum Zn and
childhood obesity, with disputable results [12]. Some studies reported that Zn levels were
lower in children with overweight/obesity [12,114]. DiMartino et al. [122] found that in the
study population, BMI was significantly higher compared to the control group, and serum Zn
concentration was significantly lower in the same groups. Similar findings were reported by
Marreiro et al. [123] and Garcia et al. [64], which observed higher insulin resistance in children
with low Zn concentration, which is related to an increased obesity risk.
It was also reported that children with overweight/obesity have significantly lower
salivary zinc levels and a higher caries risk [124].
However, Weisstaub et al. [125] observed no significant relationships between serum
Zn concentration and body weight in children. Cozzolino et al. [123] and Jacksic et al. [120]
reported similar results analyzing the relationship between Zn nutritional status and
childhood obesity.
Children 2023, 10, 695 10 of 16

5. Conclusions
In conclusion, obesity can be associated with multiple micronutrient deficiencies due
to different mechanisms. The more relevant deficits and their causes are summarized in
Table 3.

Table 3. Possible mechanisms of deficiency.

Deficiency Possible Mechanisms of Deficiency

Poor nutritional intake
Iron Increased iron requirements for elevated blood volume for increased adipose mass
Reduced iron absorption because of enhanced inflammation
Folic Acid Poor nutritional intake
Increased requirements
Vitamin B12 Poor nutritional intake
Increased requirements
Sequestration in enlarged adipose mass
Vitamin D Reduced release from skin
Leptin mediated inhibition of renal enzyme responsible for active form of vitamin D
Children 2023, 10, x FOR PEER REVIEW 11 of 17

As can be inferred, deficits are common in patients with obesity, and it is of key
As can be to
importance inferred, deficits
identify and arecorrect
commonthem
in patients with obesity,
to prevent and it complications.
possible is of key im- In Figure 3, a
portance to identify and correct them to prevent possible complications. In Figure 3, a
flowchart is proposed for the early diagnosis and monitoring of micronutrient deficiency in
flowchart is proposed for the early diagnosis and monitoring of micronutrient deficiency
the patient
in the withobesity
patient with obesity to limit
to limit adverse
adverse effectstorelated
effects related to malnutrition.
malnutrition.

Figure 3.3.
Figure Micronutrient monitoring
Micronutrient process. process.
monitoring
It is important to underline that obesity is a multifactorial disease. Therefore, in ad-
dition to overnutrition, ethnicity and genetic polymorphisms of the metabolic pathway,
in which micronutrients are involved, can play a vital role in gaining fatty tissue. Knowing
that, correct nutritional strategies can be personalized in order to optimize the mainte-
nance of a correct weight and nutritional status.
Children 2023, 10, 695 11 of 16

It is important to underline that obesity is a multifactorial disease. Therefore, in

addition to overnutrition, ethnicity and genetic polymorphisms of the metabolic pathway,
in which micronutrients are involved, can play a vital role in gaining fatty tissue. Knowing
that, correct nutritional strategies can be personalized in order to optimize the maintenance
of a correct weight and nutritional status.
Unfortunately, only a few studies are available regarding the efficacy of oral supplemen-
tation or weight loss for treating them; thus, continuous nutritional monitoring is necessary.

Author Contributions: Conceptualization, V.C. and E.V.; methodology, V.C., E.V., C.M., M.A., F.B.,
A.L.M., C.F.T., J.D., M.T. and G.Z.; data curation, V.C. and E.V.; writing—original draft preparation,
V.C., E.V., V.C., C.M., M.A., F.B., A.L.M., C.F.T., J.D. and M.T.; writing—review and editing, V.C., E.V.
and G.Z.; supervision, V.C., E.V. and G.Z. All authors have read and agreed to the published version
of the manuscript.
Funding: This project was funded under the National Recovery and Resilience Plan (NRRP), Mission
4 Component 2 Investment 1.3-Call for proposal No. 341 of 15 March 2022 of the Italian Ministry of
University and Research funded by the European Union-NextGenerationEU. Project code PE00000003,
Concession Decree No. 1550 of 11 October 2022 was adopted by the Italian Ministry of University
and Research, CUP D93C22000890001; Project title “ON Foods-Research and innovation network on
food and nutrition Sustainability, Safety and Security-Working ON Foods”.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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