Body Mass and Glucocorticoid Response in Asthma
E. Rand Sutherland1,2, Elena Goleva3, Matthew Strand4,5, David A. Beuther1,2, and Donald Y. M. Leung3,6
1Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado;2Department of Medicine, University of Colorado,
Denver, Colorado;3Department of Pediatrics, and4Division of Biostatistics, National Jewish Medical and Research Center, Denver, Colorado;
and5Department of Preventive Medicine and Biometrics, and6Department of Pediatrics, University of Colorado, Denver, Colorado
Rationale: Obesity may alter glucocorticoid response in asthma.
Objectives: To evaluate the relationship between body mass index
(BMI, kg/m2) and glucocorticoid response in subjects with and
Methods: Nonsmoking adult subjects underwent characterization of
lung function, BMI, and spirometric response to prednisone. Dexa-
methasone (DEX, 1026M)-induced mitogen-activated protein ki-
nase phosphatase-1 (MKP-1) and baseline tumor necrosis factor
(TNF)-a expression were evaluated by polymerase chain reaction in
peripheral blood mononuclear cells (PBMCs) and bronchoalveolar
and TNF-a was analyzed.
Measurements and Main Results: A total of 45 nonsmoking adults, 33
with asthma (mean [SD] FEV1% of 70.7 [9.8]%) and 12 without
asthma were enrolled. DEX-induced PBMC MKP-1 expression was
mean (6 SEM) fold-induction of 3.11 (60.46) versus 5.27 (60.66),
respectively (P 5 0.01). In patients with asthma, regression analysis
revealed a 20.16 (60.08)-fold decrease in DEX-induced MKP-1 per
unit BMI increase (P 5 0.04). PBMC TNF-a expression increased as
(TNF-a [ng/ml])per unit BMI increase (P 5 0.01). The ratio of PBMC
log (TNF-a):DEX-induced MKP-1 also increased as BMI increased in
patients with asthma (10.09 6 0.02; P 5 0.004). In bronchoalveolar
lavage cells, DEX-induced MKP-1 expression was also reduced in
overweight/obese versus lean patients with asthma (1.36 6 0.09-
fold vs. 1.76 6 0.15-fold induction; P 5 0.05). Similar findings were
not observed in control subjects without asthma.
to dexamethasone in overweight and obese patients with asthma.
Keywords: asthma; therapy; obesity
An increasing body of literature suggests an interaction between
overweight (defined as a body mass index [BMI, kg/m2] of 25–
29.9 kg/m2) and obesity (BMI > 30 kg/m2) increase asthma
incidence (2) and skew prevalent asthma toward a more difficult-
to-control phenotype (3). Despite these observations, the mecha-
nisms by which obesity modifies asthma risk or phenotype remain
unclear, as do the clinical implications of this interaction (4).
In a subset of obese individuals, enhancement of normal
adipose tissue immune function leads to a systemic inflamma-
tory state (5), with elaboration of proinflammatory molecules,
such as leptin, tumor necrosis factor (TNF)-a, and IL-6 (6, 7),
and associated metabolic and cardiovascular complications,
such as insulin resistance and atherosclerosis. Many of these
same cytokines have also been associated with the development
of glucocorticoid (GC) insensitivity in asthma (8), and are
present in obese mice that develop airway hyperresponsiveness
after exposure to ozone or sensitization and challenge with
ovalbumin (9). This raises the possibilities both that the proin-
flammatory environment of obesity could possibly modify re-
sponse to GCs and that controller agents other than inhaled GCs
could be more appropriate for patients with asthma with co-
In this regard, two recent reports (10, 11) indicate that
overweight and obese patients with asthma may not respond as
well as their lean counterparts to inhaled GCs, the most effective
asthma controller therapy (12, 13). Peters-Golden and col-
leagues, in a post hoc analysis of clinical trials randomizing
subjects to beclomethasone, montelukast, or placebo, reported
that clinical response to beclomethasone (as reflected by asthma
control days, a composite of rescue b-agonist use, nighttime
awakenings, and concurrent asthma exacerbation) was reduced
as BMI increased, a trend not observed with montelukast (11). A
separate post hoc analysis of clinical trial data by Boulet and
Franssen also demonstrated a reduction in asthma control achieved
in response to fluticasone as BMI increased; their pooled anal-
ysis of 1,242 subjects with asthma allocated to either fluticasone,
100 mg twice daily, or fluticasone/salmeterol, 50 mg/100 mg twice
daily, suggested that obese patients with asthma treated with
GC-containing regimens were less likely to achieve asthma con-
trol than were their lean counterparts (10).
Although these reports suggest a reduction in clinical re-
sponse to GC-containing therapeutic regimens in overweight
and obese patients with asthma, the mechanisms by which this
insensitivity to GCs might occur have not been elucidated. One
potential mechanism by which this could be hypothesized to
occur is altered molecular response to GCs due to systemic
inflammation. GCs inhibit proinflammatory gene expression, in
part through negative regulation of mitogen-activated protein
kinase (MAPK) signaling pathways by molecules such as MAPK
phosphatase (MKP)-1 (14). Given that proinflammatory cyto-
kines, such as IL-1, IL-6, and TNF-a, are increased in many
obese individuals, and given that these same cytokines are
regulated by and potential regulators of p38 MAPK (14), it is
possible that this proinflammatory environment might modify
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Obesity may alter glucocorticoid (GC) response in asthma.
What This Study Adds to the Field
These data suggest that in vitro response to GCs is reduced
in overweight and obese patients with asthma. This phe-
nomenon may lead to reduced clinical efficacy of GC
therapy in patients with asthma who are overweight or
(Received in original form January 11, 2008; accepted in final form July 11, 2008)
Supported by National Institutes of Health grants HL090982 (E.R.S.), AI070140
and HL36577 (D.Y.M.L.), and M01RR000051.
Correspondence and requests for reprints should be addressed to E. Rand
Sutherland, M.D., M.P.H., National Jewish Health Center, 1400 Jackson Street,
J-220 Denver, CO 80206. E-mail: email@example.com
Am J Respir Crit Care Med
Originally Published in Press as DOI: 10.1164/rccm.200801-076OC on July 17, 2008
Internet address: www.atsjournals.org
Vol 178. pp 682–687, 2008
GC function in obese patients with asthma. We hypothesized
that overweight and obese patients with asthma would demon-
strate evidence of reduced molecular responsiveness to GCs
(manifested by reduced induction of MKP-1 expression in
response to GC treatment in vitro) in immune cells derived
from both the peripheral blood and lung, a process potentially
mediated by enhanced expression of or sensitivity to TNF-a.
We further hypothesized that this effect would be specific to
asthma, and would not be observed in overweight and obese
subjects without asthma.
We enrolled nonsmoking adults (age > 18 yr) with asthma (12),
defined by: (1) a clinical history of asthma; (2) airflow limitation
(baseline FEV1< 80% predicted); and either (3) airway hyperres-
ponsiveness (PC20 methacholine , 8mg/ml); or (4) bronchodilator
responsiveness (.12% and 200 ml improvement in FEV1after 180 mg
metered-dose inhaler albuterol). Control subjects without asthma
(normal spirometry, no history of asthma) were also enrolled. Assess-
ment of lung function and airway hyperresponsiveness were performed
according to published guidelines and interpreted according to refer-
ence values (15–18). Subjects had not received systemic GCs for 1
month or longer before evaluation, and used less than the equivalent of
800 mg inhaled beclomethasone (CFC) on a daily basis. Spirometric
GC response was determined by measuring percent change in pre-
bronchodilator FEV1after the administration of prednisone, 20 mg by
mouth twice daily for 7 days, with adherence assessed by pill count.
Subjects were categorized as GC insensitive if prebronchodilator FEV1
improved by less than 12% after oral GC challenge (19). Prednisone
absorption and clearance were examined in GC-insensitive subjects as
per Hill and colleagues (20). Subjects with impaired prednisone ab-
sorption or accelerated prednisolone clearance were excluded. BMI
was calculated as kg/m2, and subjects were characterized as lean if BMI
was less than 25 kg/m2and overweight/obese if BMI was 25 kg/m2or
greater. All participants underwent skin prick testing to 13 aeroaller-
gens and positive/negative controls, and were excluded if found to be
skin test positive.
To evaluate in vitro GC sensitivity, peripheral blood mononuclear
cells (PBMCs) were isolated from 45 ml heparinized blood by Ficoll-
Hypaque (Pharmacia Biotech, Piscataway, NJ) gradient centrifugation
(21), and (in a subset of subjects) airway cells were isolated from
bronchoalveolar lavage (BAL) (19) obtained via fiberoptic bronchos-
copy performed according to published guidelines (22). After isolation,
2 3 106cells were treated with either culture medium or dexamethasone
(DEX) 1026M for 4 hours. RNA was extracted, transcribed into cDNA,
and analyzed by real-time polymerase chain reaction via the dual-labeled
fluorigenic probe method (ABI Prism 7000; Applied Biosystems, Foster
City, CA) (23) using primers and probes for human MKP-1. TNF-a
expression was measured using similar methods both in DEX-untreated
cells and after treatment with either culture medium or DEX 1026M for
4 hours. Standard curves were generated for target genes from serial
dilutions of total cDNA of the highest expression sample, with nor-
malization of each target gene to corresponding levels of the house-
keeping genes 18sRNA and/or GAPDH in each sample. Changes in
DEX-induced MKP-1 expression were expressed as fold change (19).
Unadjusted between-group comparisons were performed using
Student’s t or chi-square tests. Log transformation was used when data
were not normally distributed. To determine the association between
BMI and biomarkers of GC response, least-squares regression was
used. To avoid overfitting the model, models were adjusted only for the
potentially confounding effects of sex. Where appropriate, analyses
were performed with and without inclusion of a single significant
outlying value. All analyses were performed using JMP 7.0 (SAS
Institute, Cary, NC).
All research was approved by the National Jewish Institutional
Review Board, with informed consent obtained from all subjects.
A total of 33 adult subjects with asthma and a mean (SD) age of
40.0 (10.9) years were recruited. Mean BMI was 28.7 (5.3) kg/m2,
with a mean FEV1% predicted of 70.7 (9.8)%. A total of 12
adult subjects without asthma were also recruited, with a mean
age of 41.7 (7.7) years and mean BMI of 27.1 (6.6) kg/m2.
Additional demographic features of the study population are
reported in Table 1.
BMI and PBMC DEX-induced MKP-1 Expression
In PBMCs from subjects with asthma, blunted induction of
MKP-1 expression by DEX (1026M) was observed in over-
weight/obese versus lean patients with asthma, with mean (6SEM)
fold-induction of 3.11 (60.46) in overweight/obese subjects versus
5.27 (60.66) in lean subjects (P 5 0.01 for the comparison;
Figure 1A). When BMI was evaluated continuously, induction
of PBMC MKP-1 expression was reduced as BMI increased,
with a mean 0.16 (60.08)-fold (P 5 0.04) reduction in MKP-1
expression observed for each one-unit increase in continuous
BMI (Figure 1B). After exclusion of a single outlying subject
from the regression model, the observed effect of BMI re-
mained statistically significant in both the categorical and con-
tinuous BMI analysis, with a reduction in the mean value in the
lean group to 4.32 (60.39) (P 5 0.02 for the comparison, cat-
egorical analysis) and a 0.10 (60.04)-fold reduction (P 5 0.03)
per unit BMI (continuous analysis). Clinical GC insensitivity
was related to blunted induction of PBMC MKP-1, with only
a 3.04 (60.53)-fold increase observed in GC-insensitive subjects
versus a 4.77 (60.58)-fold increase in GC-sensitive subjects
(P 5 0.04 for comparison), a finding not modified substantially
by exclusion of the outlier data point (4.05 6 0.34; P 5 0.03).
In contrast to subjects with asthma, subjects without asthma
did not demonstrate a relationship between BMI and DEX-
induced MKP-1 expression; comparison of MKP-1 expression
between BMI categories revealed a mean 2.83 (60.32)-fold
TABLE 1. PHYSIOLOGIC AND DEMOGRAPHIC CHARACTERISTICS OF PARTICIPANTS
(n 5 12)
(n 5 33)
Asthma, BMI , 25
(n 5 11)
Asthma, BMI > 25
(n 5 22)P Value
FEV1response to albuterol, %
FEV1response to prednisone, %
Definition of abbreviations: BMI 5 body mass index.
Data are reported as mean (SD) or percent. All P values for comparison between asthmatic BMI categories using Student’s t test, except(*)using Pearson chi-square
Sutherland, Goleva, Strand, et al.: Obesity, Asthma, and Steroid Resistance 683
induction in lean control subjects without asthma (n 5 6) versus
3.03 (60.32)-fold induction in overweight/obese control subjects
without asthma (n 5 6) (P 5 0.7 for the comparison; Figure
2A). Regression modeling indicated only a 0.01 (60.04)-fold
reduction in MKP-1 expression per unit BMI increase, a finding
that was not statistically significant (P 5 0.8; Figure 2B).
BMI, TNF-a, and MKP-1 Expression in PBMCs
TNF-a mRNA expression (ng/ml per ng/ml of GAPDH) was
assayed in a subset of PBMCs from patients with asthma (n 5
11) and control subjects without asthma (n 5 11). Increasing
BMI was associated with enhanced TNF-a mRNA expression
only in patients with asthma, and not in control subjects without
asthma, with a 0.27 (60.09) unit increase in log (TNF-a [ng/ml])
for each unit increase in BMI (P 5 0.01) in subjects with asthma
(Figure 3A), and a 0.14 (60.1) unit increase in log (TNF-a [ng/ml])
per unit BMI (P 5 0.3) in subjects without asthma (Figure 3B).
To analyze the impact of this BMI-dependent increase in TNF-
a mRNA expression, the ratio of log (TNF-a [ng/ml]) to DEX-
induced MKP-1 expression was evaluated versus BMI, and subjects
with asthma were found to manifest a significant increase in this
ratio as BMI increased (Figure 4A), with a 0.09 (60.02) increase
in the ratio per unit BMI (P 5 0.004), indicating that, in asthma,
increasing BMI is associated with an increase in TNF-a mRNA
expression relative to DEX-induced MKP-1 expression. This
effect of BMI on TNF-a mRNA and DEX-induced MKP-1
expression was not observed in subjects without asthma (Figure
4B), in whom the unit increase in the ratio with increasing BMI
was 0.06 (60.04) per unit BMI (P 5 0.2). Of note, the degree of
DEX-induced suppression of TNF-a mRNA expression was
similar between subjects with and without asthma (5.41 6 0.74-
fold vs. 5.84 6 0.71-fold suppression; P 5 0.7), and did not differ
within these groups according to BMI. This suggests that the
differential relationship between baseline TNF-a mRNA and
the ability of DEX to induce MKP-1 expression in patients with
asthma versus subjects without asthma was not due to a differ-
ential relationship effect of GCs on TNF-a mRNA expression
in these two groups.
MKP-1 and TNF-a Expression in BAL Cells of Subjects
To explore whether similar alterations of DEX-induced MKP-1
expression were operative in the airways of patients with
asthma, in addition to the peripheral blood, a subset of subjects
with asthma (n 5 11) underwent fiberoptic bronchoscopy with
BAL, with analysis of MKP-1 and TNF-a mRNA expression in
BAL immune cells. No difference in BAL cell yield or differ-
ential was found between overweight/obese and lean patients
with asthma (data not shown). As was observed in PBMCs,
DEX-induced MKP-1 expression differed between BMI catego-
ries, with a 1.36 (6 0.09)-fold induction in overweight and obese
subjects versus a 1.76 (6 0.15)-fold induction in lean subjects
Figure 1. (A) Reduced dexamethasone (DEX)-induced mitogen-activated
protein kinase phosphatase (MKP)-1 expression in peripheral blood
mononuclear cells (PBMCs) from overweight/obese (gray) versus lean
(black) subjects with asthma. Data are presented as mean 6 SEM. (B)
PBMCs from patients with asthma demonstrates significantly reduced
DEX-induced MKP-1 expression with increased body mass index (BMI).
Lines represent regression with (solid line) and without outlying data
peripheral blood mononuclear cells (PBMCs) of lean (black) versus
overweight/obese (gray) subjects without asthma. Data are presented
as mean 6 SEM. (B) PBMCs from subjects without asthma do not
demonstrate significantly reduced DEX-induced MKP-1 expression with
increased body mass index (BMI).
(A) Dexamethasone (DEX)-induced MKP-1 expression in
684 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 178 2008
(P 5 0.05 for comparison; Figure 5A). Furthermore, DEX-
induced MKP-1 expression in BAL cells was reduced as BMI
increased (Figure 5B), with a 0.04 (60.01)-fold reduction (P 5
0.03) in BAL cell MKP-1 expression observed for each unit
increase in continuous BMI. A trend toward increased expression
of TNF-a by BAL cells was observed as BMI increased, with
a 0.23 (60.09)-unit increase (P 5 0.03) in log (TNF-a) for every
one-unit increase in BMI after exclusion of a single outlier
(inclusion of the outlier yielded a similar estimate of effect
[0.21 6 0.12], but with P 5 0.1).
These data indicate that in vitro biomarkers of GC insensitivity
increase in both the lung and peripheral blood as body mass
increases in individuals with asthma, but not in control subjects
without asthma. This effect is manifested by reduced induction
of MKP-1 expression in response to DEX in both PBMCs and
BAL cells, and is related to enhanced expression of TNF-a in
both peripheral and lung immune cells as body mass increases,
suggesting a scenario in which one or more molecular pathways
governing GC responses are modified in both the airway and
peripheral blood in overweight and obese patients with asthma.
These findings are statistically robust, particularly with
regard to the findings in PBMCs. Although our BAL data are
restricted to a smaller subset of the participants with asthma,
the sample facilitated detection of differences in the BAL that
mirrored our findings in the peripheral blood, suggesting that
the mechanisms underlying altered MKP-1 and TNF-a expres-
sion are operative in the lung as well. With regard to limitations
of this work, it should be noted that subjects with asthma
manifested a clinically significant degree of airflow limitation,
suggesting that we have evaluated a population of patients with
moderate-to-severe asthma, and raising the possibility that our
findings may not apply to subjects with mild or intermittent
asthma. This can also be interpreted as a potential strength,
however, in that it provides observations likely to be relevant to
a population of patients with asthma who are more challenging
to manage. Our evaluation of molecular biomarkers related to
GC response was focused on the MKP-1 pathway, and its
potential modulation by TNF-a, allowing the possibility that
other unmeasured mechanisms influencing GC signaling could
also be operative in overweight and obese patients with asthma.
Finally, because we relied on self-report of cigarette smoking, it
is possible (although unlikely) that some subjects could have
smoked during the study—a behavior known to modify oral GC
patients with asthma demonstrate significantly increased log (TNF-a)
mRNA expression with increasing body mass index (BMI). (B) PBMCs
from subjects without asthma do not demonstrate significantly in-
creased log (TNF-a) mRNA expression with increasing BMI.
(A) Peripheral blood mononuclear cells (PBMCs) from
patients with asthma demonstrate a significantly increased ratio of
log (TNF-a) mRNA to dexamethasone (DEX)-induced MKP-1 expres-
sion with increasing body mass index (BMI). (B) PBMCs from subjects
without asthma do not demonstrate a significantly increased ratio of
log (TNF-a) mRNA to DEX-induced MKP-1 expression with increasing
(A) Peripheral blood mononuclear cells (PBMCs) from
Sutherland, Goleva, Strand, et al.: Obesity, Asthma, and Steroid Resistance 685
As noted previously, the mechanisms by which obesity exerts
its effects on asthma remain unclear (4), although potential
interactions other than an effect on response to therapy include
an increased risk of developing asthma in the setting of obesity,
or a skewing toward a more severe phenotype in the overweight
or obese individual with asthma. A recent meta-analysis (2) of
prospective epidemiologic studies of BMI and asthma incidence
indicated that overweight and obesity increase asthma incidence,
with a statistically significant increase in the overall odds ratio for
incident asthma in overweight and obese subjects to approxi-
mately 1.5, along with the suggestion of dose dependency in
asthma risk as BMI increased, a phenomenon echoed in the
findings of this study with regard to GC response. Studies of the
relationship between BMI and asthma in patients with prevalent
asthma are less common, but a recent report from the National
Heart, Lung, and Blood Institute–funded Severe Asthma Re-
search Program (25) indicated that, in approximately 250 subjects
with severe asthma (26), obesity was not more prevalent in
severe versus moderate asthma, leading to questions about the
role of obesity as a modifier of asthma severity.
Most relevant to our data is the possibility that the in-
flammatory environment in obesity modifies either clinical or
biologic response to GCs. In obesity, enhancement of normal
adipose tissue immune function leads to a systemic inflamma-
tory state (5), and many of the cytokines found to be elevated in
obesity-related systemic inflammation are also associated with
development of GC insensitivity in asthma (8), and may be
critical components of the mechanisms by which this phenom-
enon occurs in overweight and obese patients with asthma. The
mechanisms of GC insensitivity are complex, reflecting the
multiple steps involved in GC action, but most important with
regard to our findings are the effects of MAPK activation on
GC receptor function. Phosphorylation modulates the function
of the GC receptor (27, 28), and prior studies have demon-
strated that cytokine-induced phosphorylation of the GC re-
ceptor, mediated by p38 MAPK or other pathways, is associated
with loss of GCR nuclear translocation and reduced respon-
siveness of T cells to DEX (29, 30). GCs have also been
reported to increase expression of a key regulator of MAPK
inactivation, MKP-1 (14, 31, 32). The observed attenuation of
MKP-1 expression in overweight and obese patients with
asthma may allow persistent MAPK activation (14), thereby
reducing molecular response to GCs and resulting in an asso-
ciated reduced clinical response to these agents.
Research over the last decade has demonstrated that TNF-a
is overexpressed in the adipose tissue and muscle of obese
humans (33–36), a phenomenon that may be of relevance to
the treatment of patients with GC-insensitive asthma, both with
regard to the potential impact on MAPK signaling pathways
noted in the INTRODUCTION, and with regard to the findings of the
recent clinical trial by Berry and colleagues, which demonstrated
an increase in expression of membrane-bound TNF-a, TNF-a
receptor 1, and TNF-a–converting enzyme in PBMCs from
patients with severe asthma, in which clinical surrogates of GC
insensitivity are the major defining criteria (26). This study dem-
onstrated a beneficial effect of soluble TNF-a receptor etanercept
in these patients, as shown by improvements in airway hyper-
responsiveness, FEV1, and asthma-related quality of life (37),
raising the possibility that controller agents other than cortico-
steroids may be more appropriate for patients with asthma char-
acterized by obesity and GC insensitivity. Although our data
are not conclusive, they do suggest that increased TNF-a in
overweight and obese patients with asthma might be one signal
by which down-regulation of MKP-1 expression is controlled.
the mechanisms by which overweight and obesity modify re-
has identified but one potential mechanism by which obesity
of this phenomenon may help identify asthma patients at risk for
prevalent subgroup of patients with asthma.
Conflict of Interest Statement: E.R.S. served as an advisor or consultant to Dey,
GlaxoSmithKline, and Schering-Plough, and received grant funding from Dey,
GlaxoSmithKline, and Novartis between 2005 and 2008. E.G. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. M.S. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. D.A.B. has received
$25,000 in investigator-initiated grant support from Merck & Co. D.Y.M.L. does
not have a financial relationship with a commercial entity that has an interest in
the subject of this manuscript.
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