Pediatric Obesity-Related Asthma_ The Role of Metabolic Dysregulation - PMC

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Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation - PMC
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Pediatrics. 2016 May;137(5):e20150812. doi: 10.1542/peds.2015-0812
Pediatric Obesity-Related Asthma: The Role of Metabolic

Dysregulation
Nandini Vijayakanthi a, John M Greally a,b,c, Deepa Rastogi a,✉
Author information Article notes Copyright and License information

PMCID: PMC4845863 PMID: 27244776
Abstract
The burden of obesity-related asthma among children, particularly among ethnic minorities,
necessitates an improved understanding of the underlying disease mechanisms. Although
obesity is an independent risk factor for asthma, not all obese children develop asthma. Several
recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle,
mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma
pathophysiology. Here, we review these recent studies and emerging scientific evidence that
suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also
review the genetic and epigenetic factors that may underlie susceptibility to metabolic
dysregulation and associated pulmonary morbidity among children. Lastly, we identify
knowledge gaps that need further exploration to better define pathways that will allow
development of primary preventive strategies for obesity-related asthma in children.
Pediatric obesity is a major public health issue that has reached epidemic proportions, affecting
∼18% of school-going children in the United States.1 Although the overall prevalence of
pediatric obesity has increased, prevalence rates differ by age, gender, and ethnicity1 and are
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2/12/24, 9:59 p.m. Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation - PMC
partly determined by sociodemographic factors.2 Notably, obesity is more prevalent among

Hispanic and African American children than their non-Hispanic white counterparts.1
Asthma, another chronic pediatric disease with increasing prevalence over the past 3 decades,
affects ∼10% of all school-age children in the United States.3 Racial and ethnic differences
evident in the prevalence of obesity overlap with those of asthma; namely, asthma is more
common among African Americans and Hispanics, particularly Puerto Ricans, compared with
non-Hispanic white children.3 The increase in asthma prevalence is likely multifactorial,
ranging from environmental factors including early-life exposures to allergens to caregiver
issues including low caregiver asthma management self-efficacy and empowerment.4 Similar
environmental factors including increased built area with decreased outdoor play, increased
screen time, increased intake of high-calorie foods, and caregiver food choices play a role in
high childhood obesity prevalence.5
Over the past decade, many cross-sectional and prospective epidemiologic studies have found
an association between pediatric obesity and asthma.6–12 A recent meta-analysis, including 6
prospective cohort studies on the effect of body weight on future risk of asthma, found a
twofold increased risk in obese children compared with normal-weight children,12 suggesting
that obesity is an independent risk factor for childhood asthma.12 Clinical studies also suggest
that obesity-related asthma is distinct from normal-weight asthma. Obesity-related asthma is
associated with decreased medication responsiveness13 and poor disease control,14–16
particularly among ethnic minority children,14,15 contributing to increased health care
expenditure. However, the mechanisms that underlie these epidemiologic and clinical
associations are poorly understood, and this gap precludes scientific advancement toward
development of targeted therapies. Here, we review recent scientific studies that begin to
elucidate the potential role of metabolic dysregulation and its associated inflammation in
pediatric obesity-related asthma. It is important to note that although the majority of studies
included in this review defined obesity as BMI >95th percentile, some combined current
definitions of overweight and obese (BMI >85th percentile). Moreover, this review focuses on
mechanisms underlying obesity-related asthma, rather than incident obesity among children
with asthma.
Mechanisms Linking Obesity and Asthma
Many mechanisms may underlie the obesity-asthma association (Fig 1). They range from
obesity-mediated alteration of pulmonary function, due to the mechanical truncal fat load
and/or inflammation,17 alteration in macro- and micronutrient intake,18 and a sedentary
lifestyle and its associated obesogenic behaviors.19 Furthermore, immunomodulatory effects of
obesity, mediated by adipocytokines including leptin, have also been postulated to underlie

asthma in obese children.20,21 However, because not all obese children develop asthma, these
factors may play a role, but do not explain the higher predisposition for pulmonary morbidity
in some, but not other, obese children. Therefore, there is need for better identification of key
molecules and biomarkers that may predict asthma development among at-risk obese children.
FIGURE 1.
🔍
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Mechanisms proposed to underlie pediatric obesity-related asthma. This figure

summarizes the factors associated with obesity-related asthma in the context of obesity
preceding asthma. Although several factors such as genetics and epigenetics are also
associated with childhood asthma, the relationships shown in this figure are specific to
those discussed in this review.
Recently, asthma has been associated with insulin resistance,22 dyslipidemia,23,24 and
metabolic syndrome,25 measures of metabolic dysregulation that develop in some but not all
obese children.26,27 Moreover, genetic and epigenetic differences in molecules involved in
metabolic dysregulation and its associated inflammation have been found in the context of
obesity-related asthma. In this review, we initially summarize the better-investigated

mechanisms such as the mechanical effect of truncal adiposity on pulmonary function and the
association of sedentary lifestyle and dietary intake with obesity-related asthma. We then
discuss more recent literature on the association of obesity-mediated inflammation and
metabolic dysregulation with pediatric obesity-related asthma and its genetic and epigenetic
footprint (Fig 1), which together begin to identify key molecules that likely underlie the
complex pathophysiology of obesity-related asthma.
Mechanical Effect of Obesity on Pulmonary Mechanics and Asthma
Obesity, and its related measure, truncal adiposity,28–30 have been associated with asthma,29–
31 and pulmonary function deficits,28 including among ethnic minority children30,32 (Table 1).
Excess truncal adiposity renders a mechanical disadvantage to the diaphragm due to
mechanical fat load and is associated with decreased functional residual capacity (FRC),33–35
with reduced residual volume (RV) and expiratory reserve volume (ERV).33–37 Lower FRC
influences bronchial smooth muscle stretch, especially at the end of tidal volume exhalation,
which leads to perception of increased respiratory effort with normal inspiration.38 Although
obese children have higher forced expiratory volume in 1 second (FEV1) and forced vital
capacity (FVC)39,40 than normal-weight children, the combination of mechanical restriction
and low lung volumes predispose obese children to present with lower FEV1/FVC ratio,33
reduced even compared with their normal-weight counterparts32,39,41 (Table 1). However,
unlike normal-weight asthma, obese asthmatic children have reduced FRC with low lung
volumes.33

TABLE 1.
Summary of Pediatric Studies Reporting an Association Between General or Truncal

Adiposity and Asthma
Study Study Obesity Sample Age, y, Ethnicity Finding

Design Definition/ Size, n (Range/Mean
BMI ± SD)
Analysis
Tantisira et CS BMI >95th 1041 5–12 Whites Decrease in
al, 200339 percentile (17%), FEV1/FVC
for age and Blacks ratio was
gender (17.6%), associated
Hispanic with increas
(18.8%) in BMI.
Others
(16.6%)
Perez-Padilla CS BMI >95th 6784 8–20 Mexican Increase in
et al, 200642 percentile or FEV1 and FV
BMI above but decrease
limits set by FEV1/FVC
International ratio with
Obesity Task increase in
Force BMI. Increas
more in
preadolescen
than
adolescents.
Chu et al, CS BMI >95th 14 654 14.3 ± 0.9 Taiwanese Higher FEV1
200940 percentile and FVC but
for age and lower
gender FEV1/FVC
ratio with
higher BMI.
Musaad et al, CS BMI >85th 1123 5–18 Caucasian BMI and wai
200928 percentile (57.4%), circumferenc
African were inverse


BMI ± SD)
Analysis
for age and American associated
gender (33.8%), with FEV1.
others
(8.8%)
Spathopoulos CS BM I>95th 2715 6–11 Caucasian High BMI is
et al, 200941 percentile (Greek) inversely
for age and correlated
gender with FEV1,
FVC, FEV1/F
ratio, and
FEF25%–75%.
Chen et al, CS BMI 718 6–17 Caucasian Waist
200943 analyzed as (Canadian) circumferenc
a continuous was inversel
variable associated
with
FEV1/FVC.
Consilvio et CS BMI >2 SD 118 6–9 Caucasian Obese
al, 201044 for age and (Italian) asthmatic
gender children had
low FEV1/FV
ratio.
Sidoroff et al, L BMI >98th 100 4–12 Caucasian Weight gain
201145 percentile (Finnish) associated
for age and with decreas
gender in FEV1/FVC
ratio.
Huang et al, CS BMI >95th 140 10–16 Mexican No associatio
201246 percentile between
for age and FEV1/FVC
gender ratio and BM
in asthmatic
Rastogi et al, CS BMI >95th 120 7–11 African FEV1/FVC
201233 percentile Americans ratio, and


BMI ± SD)
Analysis
for age and (50%), FEF25%–75%
gender Hispanics was lower in
(50%) obese
asthmatics
Vo et al, CS BMI >95th 980 7–20 Whites Higher FEV1
201332 percentile (16%), and FVC but
for age and African decrease in
gender Americans FEV1/FVC
(42%), and ratio with
Hispanics higher BMI.
(42%) FEV1/FVC
ratio was
lower in
overweight
and obese
African
Americans a
Hispanics, an
obese White
Jensen et al, CS BMI z score 361 8–17 Caucasian Lung volume
201347 >1.64 SD (Australian) reduced
among obese
children; ERV
reduced in
obese
asthmatics, R
and RV/TLC
ratio reduced
in obese
nonasthmati
children.
Jensen et al, CS BMI z score 48 11.9 ± 2.3 Caucasian Lean mass, n
2014 48 analyzed as (Boys) 13.6 ± (Australian) fat mass, is
a continuous 2.2 (Girls) associated
variable with FEV1,


BMI ± SD)
Analysis
FVC, and TLC
in boys and
with TLC in
girls.
Sanchez- CS BMI >95th 153 4–15 Caucasian Waist
Jimenez et al, percentile (Spanish) circumferenc
201449 for age and was inversel
gender associated
with FEV1 an
FVC.
Wang et al, CS BMI z score 646 11–12 Caucasian Higher FEV1
201450 analyzed as (British) and FVC with
a continuous higher BMI i
variable girls. Percent
truncal fat
inversely
correlated
with FEV1 an
FVC in boys
but not girls.
Rastogi et al, CS BMI >95th 168 13–18 African Truncal
201434 percentile Americans adiposity an
(42.1%), general
Hispanics adiposity we
(57.9%) associated
with reduced
FRC, RV, and
RV/TLC ratio
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CS, cross-sectional; L, longitudinal.

These studies suggest an association among truncal adiposity, asthma, and altered lung
mechanics. However, because truncal adiposity is a risk factor for metabolic dysregulation,51
we speculate that metabolic dysregulation, not investigated in these earlier studies, may have
coexisted with truncal adiposity. In keeping with this speculation, insulin resistance and
dyslipidemia were found to be predictors of FEV1/FVC ratio and ERV,34 the 2 pulmonary
function indices that are decreased among obese asthmatics, and mediated the association of
BMI and waist circumference with these indices,34 suggesting that biological factors other than
mechanical fat load may mediate the influence of obesity on pulmonary function.
Ethnicity and gender may also influence these associations. Hispanics and African Americans,
who bear a higher burden of obesity-related asthma, have greater truncal adiposity for the same
body weight than Caucasians.52 With regard to gender, although obese girls have more
symptoms53,54 and nonatopic inflammation compared with boys,47 boys have a higher
prevalence of metabolic syndrome.25 Moreover, whereas one study reported an association
between truncal fat and FEV1 and FVC only among boys,50 another study found an association
between lean mass, rather than fat mass, with FEV1, FVC, and total lung capacity (TLC) among
boys, and only with TLC in girls.48 The disparate results of these few studies highlight the need
for gender as well as ethnicity-specific investigations of the associations among mechanical fat
load, presence of metabolic dysregulation, and pulmonary function deficits linked with
pediatric obesity-related asthma.
Weight Loss
Thus far, there are only 2 studies on the effect of weight loss on obesity-related asthma in
children.48,55 Jensen et al reported an improvement in asthma control in obese asthmatics
following diet-induced weight loss.48 ERV and RV/TLC ratio and Pediatric Asthma Quality of
Life Questionnaire (PAQLQ) symptom and emotional domain scores also improved but did not
differ significantly from the change in the control group.48 Van Leeuwen et al reported
decreased severity of exercise-induced bronchoconstriction and improved PAQLQ scores,
particularly in the symptoms and activity domain, after weight loss.55 Moreover, limiting
caloric intake in the normal range in obese children was also associated with improvement in
asthma control and PAQLQ scores.56 Together, this limited literature suggests that weight loss
in children is associated with improvement in clinical and quality-of-life parameters. However,
there are no studies on pulmonary effects of weight loss in ethnic minority children. Because
diet-induced weight loss in children, particularly among those of minority ethnic background,
is often modest,57 other therapeutic options are needed to address obesity-mediated
pulmonary morbidity in the pediatric populations most afflicted by these diseases.
Diet and Asthma

Increased intake of processed food, high in fat and low in antioxidant content, has been
associated with asthma.58,59 Conversely, consumption of the Mediterranean diet, high in fruits
and vegetables, and omega-3 fatty acids, has been found to be protective.60–63 Therefore, the
type of fat, in addition to total fat intake, may play a role in its association with asthma.
Systemic inflammation linked to dietary fat intake may underlie these associations.64–66
Omega-6 fatty acids, including arachidonic acid (20:4 n-6) and linoleic acid (18:2 n-6), mediate
inflammation,67 whereas omega-3 fatty acids, including eicosapentaenoic acid (20:5 n-3) and
docosahexaenoic acid (22:6 n-3), are protective.67,68 Prostaglandins and leukotrienes, both of
which are arachidonic acid metabolites, have been quantified in exhaled breath condensates
from children with asthma.69 However, the extent to which asthma symptomatology and
pulmonary function improve with increased intake of omega-3 or decreased intake of omega-6
fatty acids is not well known among obese children with asthma and is being investigated in
ongoing randomized trials of omega-3 fatty acids supplementation.70
Furthermore, intake of micronutrients such as vitamins A,59,71,72 C,59,73 and E73 has been
inversely associated with asthma, whereas vitamin D insufficiency has been associated with
higher asthma disease burden74 and lower lung function.75,76 Although the exact mechanism
through which vitamin D influences asthma in obese children is not known, vitamin D does
have immunomodulatory effects77 and may influence intestinal microflora,78 mechanisms that
have been associated with asthma pathophysiology.79,80 There is also evidence to suggest that
maternal diet may influence incident childhood asthma and obesity, an aspect that has been
previously reviewed.81 Although these initial studies suggest that dietary intake may be linked
to obesity-related asthma, more research is needed to explore the various effects of dietary
macro- and micronutrients on asthma.
There is also a substantive role of parental choice82 and feeding practices83 in a child’s dietary
intake82 and behavior,83 including among Hispanics84,85 and African Americans.86 For
example, among Hispanic households, >50% of the parents reported having sugar-sweetened
beverages, and >80% reported having energy-dense foods including potato chips, cookies, cake,
or ice cream in their home.84 In keeping with these findings, weight-resilient African American
adolescents were those who consumed more fruits and vegetables and whose parents were in
the healthy weight range and provided supervision to physical activity and accessed grocery
stores with better food availability.86 Given the complex relationships between macro- and
micronutrient intake and asthma and the role of parental dietary choices and feeding practices
on dietary intake, future studies are needed to define the impact of each of these aspects of
nutritional intake on childhood asthma, including obesity-related asthma. These findings may
elucidate a role of dietary modification rather than restriction in the management of obesity-
related asthma,18,87 particularly in those of minority ethnicities, given their higher disease
burden and modest effectiveness of weight loss.
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Sedentary Lifestyle, Physical Fitness, and Asthma
Obese children also tend to have a sedentary lifestyle. Increased use of electronic gadgets,
television watching, and video games has decreased outdoor play time and been linked with
overweight and obesity in children.88,89 The number of hours playing video games and
watching TV directly correlate with asthma incidence and prevalence among children.19,90
Sedentary lifestyle and decreased physical fitness cause central obesity and thereby predispose
children to asthma.91,92 Moreover, the association of functional exercise capacity among obese
asthmatics with BMI and not with FEV1/FVC ratio, suggests a larger role of adiposity in
exercise limitation among obese asthmatics.93 Together these associations highlight the
importance of addressing such obesogenic behaviors early in life to prevent the development of
obesity and its associated pulmonary morbidities.
Obesity-Mediated Inflammation and Asthma
Obesity is recognized to be a low-grade inflammatory state. Obesity-mediated inflammation

has been associated with asthma and pulmonary function deficits.33 Adipocyte hypoxia due to
delayed neovascularization of adipose tissue is the most potent known stimulus for initiation of
adipose tissue inflammation94 and release of leptin, a proinflammatory adipokine. The
proinflammatory cascade comprises a shift in the macrophage pool from the antiinflammatory
M2 macrophages to the proinflammatory M1 macrophages (Fig 1).95 Additionally, there is
enhanced CD4+ T lymphocyte proliferation and differentiation into Th1 cells (Fig 1), with
increased interferon-γ (IFN-γ), interleukin (IL)-6, and tumor necrosis factor (TNF)
production.95 This correlates with suppression of Th2 cells and decrease in T regulatory
cells.96 To maintain homeostasis, the proinflammatory effect of leptin is offset by
antiinflammatory adipokines, including adiponectin, and omentin and the related
antiinflammatory cytokine IL-10.97–99
Clinical studies have demonstrated elevated leptin21 and reduced adiponectin levels in obese
children33,100 compared with nonobese children with asthma, suggesting that obesity-induced
changes in the systemic adipocytokine milieu may underlie asthma in children.101 Serum leptin
levels correlate with higher Th1/Th2 cell ratio,33,102 and higher serum IFN-γ levels,21
indicative of nonatopic inflammation among obese asthmatic children compared with their
nonobese counterparts, including in ethnic minority children.33,103 These nonatopic systemic
inflammatory patterns correlate with lower airway obstruction33 and exercise-induced
bronchoconstriction104 among obese asthmatic children and persist into adulthood.105 These
findings support epidemiologic reports of a lack of association between childhood obesity-
related asthma and atopy7,101,106 and higher prevalence of noneosinophilic asthma in obese
children.47 However, there are also reports of increased atopy among obese children,53,54,107
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including associations among BMI, atopic sensitization, and bronchial hyperresponsiveness,53

as well as among BMI, atopy, cough, and wheeze,54 particularly among girls53,54 (Table 2).
Similar disparate links among obesity, asthma, and atopy are also observed in investigations of
allergic airway inflammation using fractional exhaled nitric oxide (FeNO) and obesity-related
asthma. Whereas BMI was associated with asthma only among children with low FeNO,108 BMI
was associated with higher asthma disease burden among those with high FeNO108 (Table 2).
Furthermore, FeNO was not associated with asthma among obese children,109 and a significant
association between BMI and FeNO was observed only among nonasthmatic children.110

TABLE 2.
Summary of Pediatric Studies Reporting an Association Between Inflammatory

Mediators of Obesity and Asthma
Study Study Obesity Sample Age Range, Ethnicity Finding

Design Definition/ Size, n y
BMI
Analysis
Huang et CS BMI 1459 13.2–15.5 Taiwanese BMI was a significa
al, 199953 analyzed in predictor of atopy,
quintiles allergic symptoms,
and airway
hyperresponsivene
in teenage girls.
Von Mutius CS BMI 7370 4–17 Caucasians BMI is associated
et al, analyzed in (26.3%), with asthma, but n
20017 quartiles African with atopy, among
Americans children sampled in
(34%), NHANES III.
Mexican
Americans
(35%),
others
(4.8%)
Schachter CS BMI >95th 5993 7–12 Caucasian Higher BMI is a risk
et al, percentile factor for atopy,
200354 for age and wheeze and cough
gender girls only but not a
risk factor for
asthma or airway
hyperresponsivene
in either boys or
girls.
Leung et CS Body wt 115 7–18 Hong Kong Obesity is not
al, 2004111 >120% of associated with
the median FeNO or airway


BMI
Analysis
wt for leukotriene levels i
height asthmatic children
Santamaria CS BMI >95th 50 8–16 Caucasian No association
et al, percentile (Italian) between FeNO and
2007109 for age and obesity among
gender asthmatic children
Huang et CS BMI >95th 89 10–16 Mexican Higher markers of
al, 2008112 percentile endothelial
for age and inflammation
gender (sICAM) among
obese asthmatics.
No difference in CR
levels between
obese and normal-
weight asthmatic
children.
Michelson CS BMI z score 10 140 0–19 Caucasians BMI z score and CR
et al, analyzed as (60.6%), levels were
2009113 a African associated with
continuous Americans asthma severity
variable (14.4%), among children in
Mexicans NHANES 2001–200
(12.4%),
other
Hispanics
(6.4%),
others
(6.3%)
Visness et CS BMI >95th 16 074 2–19 Caucasians Association betwee
al, 2010106 percentile (59.9%), obesity and asthma
for age and African greater among non
gender Americans atopic children tha
(14.7%), atopic children.
Mexicans Association of CRP
(12.5%), with asthma amon

BMI
Analysis
others nonatopics mediat
(12.9%) by BMI.
Rastogi et CS BMI >95th 120 7–11 African Obese asthmatics
al, 201233 percentile Americans had systemic Th1
for age and (50%), polarization, which
gender Hispanics directly correlated
(50%) with lower airway
obstruction.
Huang et CS BMI >95th 178 10–16 Mexican Obese asthmatics
al, 201246 percentile and nonasthmatics
for age and had higher
gender plasminogen
activator inhibitor,
fibrinogen, and BM
with inversely
correlated with
FEV1/FVC ratio.
Khan et al, CS BMI >95th 124 12–20 African hsCRP highest in
2012114 percentile Americans obese asthmatics
for age and (41%), compared with
gender Hispanics obese
(59%) nonasthmatics,
normal-weight
asthmatics, and
healthy controls
Sah PK et CS BMI >95th 269 6–17 Whites Obese asthmatics
al, 2013115 percentile (32.7%), with poor asthma
for age and nonwhites control had lower
gender (67.3%) serum levels of IL-5
IL-13, and IL-10.
Youssef et CS BMI >95th 70 9.3 ± 2.5 Caucasian Obese asthmatics
al, 2013102 percentile (obese (Egyptian) had high asthma
for age and asthmatics) severity, lower FEV
gender 10.4 ± 1.3 Serum leptin levels


BMI
Analysis
(nonobese correlated with
asthmatics) serum IFNγ levels,
10.7 ± 2.9 which directly
(controls) correlated with
asthma symptoms
and inversely
correlated with FEV
among obese
asthmatic children
Jensen et CS BMI z score 361 8–17 Caucasian Noneosinophilic
al, 201347 >1.64 SD (Australian) asthma more
prevalent in obese
asthmatic girls than
boys.
Han et al, CS BMI >95th 2681 6–17 Caucasians Adiposity indicator
2014108 percentile (33.3%), are associated with
for age and African asthma among
gender Americans children with low
(20.2%), FeNO. Adiposity
Hispanics indicators are
(40.2%), associated with
others worse asthma
(5.7%) morbidity in those
with high FeNO
among children in
NHANES 2007–201
Rastogi et CS BMI >95th 168 13–18 African Th1 polarization an
al, 2015103 percentile Americans monocyte activatio
for age and (42.1%), correlated with
gender Hispanics metabolic
(57.9%) abnormalities in
obese asthmatics.
Association of
monocyte activatio
with pulmonary


BMI
Analysis
function was
mediated by BMI,
whereas that of Th
polarization was
mediated by insulin
resistance.
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CRP, C-reactive protein; CS, cross-sectional; HsCRP, high-sensitivity C-reactive protein.
It is hypothesized that these disparate reports either support heterogeneity in the

pathophysiology of obesity-related asthma116 or are reflective of inherent differences in
disease severity.108 As noted in normal-weight asthma, although classic asthma is atopic,
involving eosinophils and Th2 cells, severe asthma, even among normal-weight individuals, is
nonatopic, mediated by neutrophils.117 Whether similar variability in the involvement of
innate immune pathways comprising Th1 cells, M1 macrophages, and neutrophils occurs in the
pathogenesis of obesity-related asthma needs further investigation. Recent literature
highlighting the role of metabolic dysregulation in obesity-related asthma118 may begin to
clarify these issues because differential inflammation among obese individuals with or without
metabolic dysregulation may partly underlie the heterogeneity of the obese asthma phenotype.
Obese asthmatics are also less responsive to steroid treatments.13,119 Peripheral blood
mononuclear cells from obese asthmatics had lower production of antiinflammatory enzymes
in response to dexamethasone,119 and increased TNF production, which directly correlated
with BMI.119 Similar trends were also observed in bronchoalveolar lavage cells obtained from
obese asthmatics.119 On the basis of these reports, it can be speculated that obese asthmatics
may respond to nonsteroidal antiinflammatory agents including montelukast or etanercept, a
TNF inhibitor,120,121 an aspect that needs further investigation.
Obesity-Mediated Metabolic Dysregulation and Asthma

Association With Insulin Resistance
Obese children, particularly those of ethnic minorities, are predisposed to develop insulin
resistance,122 a precursor to diabetes,123 that is associated with systemic hyperinsulinemia.122
Our review of the recent literature highlights that metabolic dysregulation plays a role in
pediatric obesity-related asthma (Table 3). Higher prevalence124 and degree of insulin
resistance22 and higher prevalence of its surrogate marker, acanthosis nigricans,23 and
metabolic syndrome,25 have been reported among children with asthma compared with their
nonasthmatic counterparts. Insulin resistance correlates with the proinflammatory markers
leptin and IL-6124 and is found to be a predictor of both lower airway obstruction and reduced
lung volumes, 2 distinct measures of lung function deficits, independent of general and truncal
adiposity.34

TABLE 3.
Summary of Pediatric Studies Reporting an Association Between Metabolic

Dysregulation and Asthma
Study Study Obesity Sample Age, y Ethnicity Finding

Design Definition Size, n (Range/Mean
± SD)
Al- CS BMI >95th 188 4–20 Not Hypercholesterolem
Shawwa, percentile available is associated with
et al, for age and higher asthma
200624 gender frequency,
independent of
obesity.
Al- CS BMI >95th 415 2–18 Caucasian Obese asthmatics h
Shawwa percentile (40.5%), higher levels of
et al, for age and African insulin resistance
200722 gender Americans compared with
(38.5%), morbidly obese
others nonasthmatics.
(21%) Asthma prevalence
directly correlated
with insulin levels.
Arshi et CS BMI 31 6–17.9 Caucasian Insulin resistance
al, analyzed (Australian) was present among
2010124 as a atopic asthmatics,
continuous which correlated w
variable leptin and IL-6 leve
Del-Rio- CS BMI >95th 443 12–14.2 Mexican Prevalence of
Navarro percentile metabolic syndrom
et al, for age and was higher among
201025 gender obese asthmatic bo
not girls.
Cottrell CS BMI 17 994 4–12 Whites Asthma is associate
et al, >95th– (90.7%), with dyslipidemia
201123 98.9th African and insulin
percentile American

± SD)
for age and (2.3%), resistance,
gender others independent of BM
(0.9%)
Lee et CS BMI 2082 8.5 ± 1.7 Taiwanese Diet with high intak
al, analyzed of fat and simple
201258 as a sugars was
continuous associated with
variable increased risk of
asthma.
Chen et CS BMI >95th 462 10–15 Taiwanese Asthma was
al, percentile associated with
2013125 for age and higher levels of tota
gender cholesterol and low
density lipoprotein,
particularly in
overweight and obe
children.
Rastogi CS BMI >95th 168 13–18 African Dyslipidemia and
et al, percentile Americans insulin resistance
201434 for age and (42.1%), were predictors of
gender Hispanics pulmonary function
(57.9%) deficits, independen
of adiposity
Sanchez- CS BMI >95th 153 4–15 Caucasian Insulin levels were
Jimenez percentile (Spanish) associated with
et al, for age and allergen sensitizatio
201449 gender among asthmatics.
Rastogi CS BMI >95th 168 13–18 African Th1 polarization an
et al, percentile Americans monocyte activation
2015103 for age and (42.1%), correlated with
gender Hispanics metabolic
(57.9%) abnormalities. Insu
resistance mediated
the association of T


± SD)
polarization with
pulmonary function
Open in a new tab
CS, cross-sectional.
Systemic inflammation, associated with insulin resistance, may be one of the mechanisms
through which insulin resistance contributes to impaired lung function and asthma phenotype.
In addition to its role in glucose metabolism, insulin has antiinflammatory effects.126 Insulin
supplementation has been associated with attenuation of lipopolysaccharide-induced acute
lung injury in a murine model, with decreased TNF, IL-1β, and IL-6 in the bronchoalveolar
lavage fluid.127 Obesity-mediated inhibition of insulin signaling, a key mechanism underlying
insulin resistance, is associated with adipose tissue inflammation with activation of Th1 cells
and innate immune pathways, involving macrophages.128 Recent studies have found that insulin
resistance mediates the association of systemic Th1 polarization with obesity-mediated
pulmonary function deficits among ethnic minority children.103 Given these initial
investigations into the association among insulin resistance, inflammation, and pulmonary
function impairment, further study of the underlying immunometabolic pathways is needed to
determine the mechanism through which insulin resistance contributes to the obese asthma
phenotype.
Another mechanism is the influence of insulin on airway smooth muscle (ASM). Insulin
resistance is associated with airway hyperreactivity due to increased ASM contractility.129
Several mechanisms underlie this observation. Hyperinsulinemia increases laminin expression
in bovine ASM cells via phospho-inositide-3 kinase (PI3K)/Akt dependent pathway.129 Insulin
resistance also increases free insulin-like growth factor, which is associated with ASM
proliferation.130 Furthermore, insulin may increase airway hyperresponsiveness by modulating
parasympathetic stimulation, studied in an obese rat model.131 These studies suggest that
insulin resistance and associated hyperinsulinemia influence ASM cell function through
different mechanisms, with the end result of increased bronchial hyperresponsiveness.
Translational studies are now needed to study the role of each of these pathways in ASM cells
obtained from obese asthmatics. We believe that better understanding of these pathways will

be paradigm changing by potentially extending the use of metformin, routinely prescribed for
insulin resistance, into management of obesity-related asthma.132
Association With Dyslipidemia
Similar to insulin resistance, links have been described between dyslipidemia and wheezing in
adults133 and asthma among children23 (Table 3). High-density lipoprotein (HDL) has been
found to have a protective effect on pulmonary function indices in obese urban adolescents.34
There is preliminary evidence to suggest that this effect may be mediated in part by the
protective effect of HDL on monocyte activation.103 There is also increasing evidence to
suggest that the origins of the association of diet-induced metabolic dysregulation and
pulmonary morbidity may start as early as in utero. For instance, altered fat intake, with low
intake of poly-unsaturated fatty acids in the mother, has been associated with an increased
predisposition to asthma among the offspring.134 Thus, altered fat intake and dyslipidemia,
irrespective of BMI, may be risk factors for airway inflammation and hyperreactive airways.23
Many mechanisms, including inflammation, may underlie the association between dyslipidemia
and asthma. High fat intake in an adult cohort was associated with increased neutrophilic
airway inflammation and an attenuated response to bronchodilators.135 Similarly, a high-fat
meal, associated with elevated triglycerides and reduced HDL after 2 hours, correlated with
increased levels of FeNO.136 Because high-fat diet is associated with decreased consumption of
antioxidants, it may make the lung susceptible for oxidative damage and inflammation.18 These
pathways have not been studied in children, and thus the mechanisms underlying the
association of dyslipidemia with asthma in children are relatively unknown.
Crosstalk Between Genes and Environment in Obesity-Related Asthma
The associations of asthma with obesogenic lifestyles and obesity-mediated metabolic

dysregulation, inflammation, and mechanical fat load suggest that these environmentally
mediated exposures and clinical states may influence the lungs via epigenetic
mechanisms.137,138 However, it is also evident that not all obese children with metabolic
dysregulation or inflammation develop asthma, suggesting that differences in genetic
susceptibility may also underlie the development of pulmonary morbidity in only some obese
children. Although few studies have investigated the genetics or epigenetics of obesity-related
asthma, we discuss the existing literature and the direction of association observed in these
initial investigations.
Epigenetics of Obesity-Related Asthma

Epigenetic differences have been identified in context of both obesity139,140 and asthma141,142
compared with healthy controls. Among obese children, differences in DNA methylation, an
epigenetic regulatory mechanism, were identified at 5 sites at the FTO gene, variants of which
are strongly associated with obesity.139 Similarly, hypomethylation of DNA at the IL-4 gene
promoter and hypermethylation of the IFNγ promoter have been observed in children with
atopic asthma.143 Genome-wide studies have also identified differential methylation of several
genes associated with atopic inflammation among asthmatics.141 However, only 1 study defined
differences in DNA methylation among children with obesity-related asthma compared with
children with normal-weight asthma, obesity without asthma, and healthy controls.144 In this
study, specific DNA methylation patterns were associated with childhood obesity-related
asthma. Gene promoters encoding for molecules involved in Th1 polarization, chemokine (C-C
motif) ligand 5 (CCL5), interleukin 2 receptor α chain (IL2RA), and T-box transcription factor
(TBX21), were hypomethylated, whereas those encoding for receptors for immunoglobulin E
and TGFB1, involved in Th1 cell inhibition, were hypermethylated,144 suggesting DNA
methylation plays a role in Th1 polarized systemic inflammation. Additionally, molecules such
as PI3K and PPARγ, involved in glucose metabolism in T cells,145 and lipid uptake, respectively,
were hypomethylated in obese asthmatics relative to obese nonasthmatics. These findings
suggest that molecules associated with both inflammation and metabolic dysregulation are
differentially methylated among obese asthmatics. Because dietary intake and nutrients modify
DNA methylation,138 these pilot results highlight the need for additional studies to investigate
the effect of diet modification and related weight loss on DNA methylation and its association
with insulin resistance, dyslipidemia, and systemic inflammation among obese asthmatics.
Genetics of Obesity-Related Asthma
While few conclusive studies have identified susceptibility loci for development of asthma
among obese children,146 a common 16p11.2 inversion that may protect against susceptibility
to asthma and obesity has been identified in adults.147 This inversion, found in 10% of Africans
and ∼50% of Europeans, is associated with increased expression of obesity-associated proteins
including apolipoprotein B (APOB48R) and SH2B1, which inhibit type 1 interferon and IL27.
This inversion explains ∼40% of the population-attributable risk for joint susceptibility to
obesity and asthma. Additional genes including the β2-adrenergic receptor gene
(ADRB2),148,149 the TNF gene,150,151 and the lymphotoxin-α (LTA) gene152,153 have been
associated in both obesity and asthma in children. However, the limited number of these studies
highlights the paucity of data on genetic susceptibility for obesity-related asthma. Moreover,
given the ethnic differences in the prevalence of pediatric obesity-related asthma, studies are
needed to identify the role, if any, of ancestry-specific genetic polymorphisms that may explain
the greater disease burden among Hispanics and African Americans.

Recommendations for Clinical Practice
Together, these studies on the mechanisms underlying obesity-related asthma suggest a

complex interplay among mechanical fat load of truncal adiposity, metabolic dysregulation, and
inflammation. On the basis of these studies, we suggest that pediatricians consider
implementing the following in their clinical practice:
1. Routine evaluation for truncal adiposity by measuring waist circumference among their
patients who are overweight/obese
2. Routine evaluation for metabolic dysregulation, specifically for insulin resistance and
dyslipidemia in fasting blood among obese children,154 particularly in those with truncal
adiposity
3. Elucidation of respiratory symptoms among obese children, particularly those with
truncal adiposity, and/or metabolic dysregulation
4. Testing for pulmonary function deficits among obese children, especially those with
truncal adiposity, and/or metabolic dysregulation
5. Ensure good asthma control and encourage physical activity for weight control because
there is no therapy specific for obesity-related asthma, and these children are
suboptimally responsive to inhaled steroids
6. Encourage parents to monitor dietary intake, with increased intake of foods included in a
Mediterranean diet and decreased consumption of processed foods
Road Map for Future
In summary, obesity-related asthma is an emerging health problem among children. Although it

appears to be distinct from normal-weight asthma, further investigations are needed to better
define its pathophysiology. The association of obesity-related asthma with insulin resistance
and dyslipidemia provides directionality to future investigations into underlying pathways that
may be amenable to pharmacologic modification. Because these metabolic abnormalities are
obesity-mediated but do not develop in all obese children, quantification of these metabolic
biomarkers may help identify obese children at risk for developing obesity-mediated
pulmonary morbidity. Moreover, the association of asthma with diet, particularly fat and
vitamin intake, and the association of diet with DNA methylation highlights the need for studies
to better define the links between diet and epigenetics of obesity-related asthma, in the
presence of insulin resistance and/or dyslipidemia. Given the modest effect of weight loss
interventions among children and lack of studies on the pulmonary effects of bariatric surgery,
these future studies will identify mechanisms underlying the beneficial effects of nutrients and
thereby facilitate the development of targeted diets for obese children at risk for developing
obesity-related asthma, specifically those of Hispanic and African American ancestry.

Identification of ancestry-specific genetic susceptibility will not only shed light on the reasons
underlying increased disease burden among certain populations but may facilitate the
development of primary prevention strategies for those identified to be genetically susceptible
to obesity and its associated morbidities. Because obese asthmatics are suboptimally
responsive to current asthma medications, identification of mechanisms underlying obesity-
related asthma will provide direction for development of both preventative strategies and
targeted therapy.
Glossary
ASM
airway smooth muscle
ERV
expiratory reserve volume
FeNO
fractional exhaled nitric oxide
FEV1
forced expiratory volume in 1 second
FRC
functional residual capacity
FVC
forced vital capacity
HDL
high-density lipoprotein
IFN-γ
interferon-γ
IL
interleukin
PAQLQ
Pediatric Asthma Quality of Life Questionnaire
RV
residual volume
Th cells
T helper cells
TLC
total lung capacity
TNF
tumor necrosis factor

Footnotes
Dr Vijayakanthi performed literature searches on the topic and subtopics for relevant articles for
inclusion and drafted and edited the manuscript; Dr Greally conceptualized the manuscript with Mr
Rastogi and critically reviewed the manuscript; Mr Rastogi conceptualized the manuscript with Dr
Greally, performed literature searches on the topic and subtopics for relevant articles for inclusion
in the manuscript, and edited the manuscript; and all authors approved the final manuscript as
submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant
to this article to disclose.
FUNDING: Dr Rastogi (K23HL118773) and Dr Greally (R01DA030317 and R21GM101880) are

supported by the National Institutes of Health. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts
of interest to disclose.
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2/12/24, 9:59 p.m.

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation - PMC

Pediatrics. 2016 May;137(5):e20150812. doi: 10.1542/peds.2015-0812

Pediatric Obesity-Related Asthma: The Role of Metabolic

Author information Article notes Copyright and License information

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partly determined by sociodemographic factors.2 Notably, obesity is more prevalent among

Mechanisms Linking Obesity and Asthma

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Mechanisms proposed to underlie pediatric obesity-related asthma. This figure

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Mechanical Effect of Obesity on Pulmonary Mechanics and Asthma

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Summary of Pediatric Studies Reporting an Association Between General or Truncal

Study Study Obesity Sample Age, y, Ethnicity Finding

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Study Study Obesity Sample Age, y, Ethnicity Finding

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Study Study Obesity Sample Age, y, Ethnicity Finding

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Study Study Obesity Sample Age, y, Ethnicity Finding

Open in a new tab

CS, cross-sectional; L, longitudinal.

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Diet and Asthma

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Sedentary Lifestyle, Physical Fitness, and Asthma

Obesity-Mediated Inflammation and Asthma

Obesity is recognized to be a low-grade inflammatory state. Obesity-mediated inflammation

including associations among BMI, atopic sensitization, and bronchial hyperresponsiveness,53

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Summary of Pediatric Studies Reporting an Association Between Inflammatory

Study Study Obesity Sample Age Range, Ethnicity Finding

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Study Study Obesity Sample Age Range, Ethnicity Finding

Study Study Obesity Sample Age Range, Ethnicity Finding

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Study Study Obesity Sample Age Range, Ethnicity Finding

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Study Study Obesity Sample Age Range, Ethnicity Finding

Open in a new tab

CRP, C-reactive protein; CS, cross-sectional; HsCRP, high-sensitivity C-reactive protein.

It is hypothesized that these disparate reports either support heterogeneity in the

Obesity-Mediated Metabolic Dysregulation and Asthma

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Association With Insulin Resistance

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Summary of Pediatric Studies Reporting an Association Between Metabolic

Study Study Obesity Sample Age, y Ethnicity Finding

Study Study Obesity Sample Age, y Ethnicity Finding

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Study Study Obesity Sample Age, y Ethnicity Finding

Open in a new tab

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Association With Dyslipidemia

Crosstalk Between Genes and Environment in Obesity-Related Asthma

The associations of asthma with obesogenic lifestyles and obesity-mediated metabolic

Epigenetics of Obesity-Related Asthma

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Genetics of Obesity-Related Asthma