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: firstname.lastname@example.org
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
4. Weiss ST, Shore S. Obesity and asthma: directions for research. Am J
Respir Crit Care Med 2004;169:963–968.
5. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin
6. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante
AW Jr. Obesity is associated with macrophage accumulation in
adipose tissue. J Clin Invest 2003;112:1796–1808.
7. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in
adipose tissue. J Clin Invest 2003;112:1785–1788.
8. Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory
cytokines regulate human glucocorticoid receptor gene expression
and lead to the accumulation of the dominant negative b isoform:
a mechanism for the generation of glucocorticoid resistance. Proc
Natl Acad Sci USA 2001;98:6865–6870.
9. Shore SA. Obesity and asthma: lessons from animal models. J Appl
10. Boulet LP, Franssen E. Influence of obesity on response to fluticasone
with or without salmeterol in moderate asthma. Respir Med 2007;101:
11. Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E, Edelman JM.
Influence of body mass index on the response to asthma controller
agents. Eur Respir J 2006;27:495–503.
12. National Institutes of Health; National Heart Lung and Blood Institute;
National Asthma Education and Prevention Program. Expert Panel
Report 3: guidelines for the diagnosis and management of asthma.
Bethesda, MD: U.S. Department of Health and Human Services;
National Institutes of Health; National Heart Lung and Blood
Institute; National Asthma Education and Prevention Program;
2007. NIH Publication No. 07-4051.
13. Global Initiative for Asthma (GINA). Global strategy for asthma man-
agement and prevention, 2006. Bethesda, MD: NHLBI. Available from:
14. Clark AR. MAP kinase phosphatase 1: a novel mediator of biological
effects of glucocorticoids? J Endocrinol 2003;178:5–12.
15. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin
CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, et al.
Guidelines for methacholine and exercise challenge testing—1999.
This official statement of the American Thoracic Society was adopted
by the ATS board of directors, July 1999. Am J Respir Crit Care Med
16. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values
from a sample of the general U.S. population. Am J Respir Crit Care
17. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A,
Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al.
Standardisation of spirometry. Eur Respir J 2005;26:319–338.
18. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R,
Coates A, van der Grinten CP, Gustafsson P, Hankinson J, et al.
Interpretative strategies for lung function tests. Eur Respir J 2005;26:
19. Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY. Increased
glucocorticoid receptor b alters steroid response in glucocorticoid-
insensitive asthma. Am J Respir Crit Care Med 2006;173:607–616.
20. Hill MR, Szefler SJ, Ball BD, Bartoszek M, Brenner AM. Monitoring
glucocorticoid therapy: a pharmacokinetic approach. Clin Pharmacol
21. Sher ER, Leung DY, Surs W, Kam JC, Zieg G, Kamada AK, Szefler SJ.
Steroid-resistant asthma: cellular mechanisms contributing to inade-
quate response to glucocorticoid therapy. J Clin Invest 1994;93:33–39.
22. Summary and recommendations of a workshop on the investigative use
of fiberoptic bronchoscopy and bronchoalveolar lavage in asthmatics.
Am Rev Respir Dis 1985;132:180–182.
23. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, Darst
MA, Gao B, Boguniewicz M, Travers JB, et al. Cytokine milieu of
atopic dermatitis, as compared to psoriasis, skin prevents induction of
innate immune response genes. J Immunol 2003;171:3262–3269.
24. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W,
Thomson NC. Cigarette smoking impairs the therapeutic response to
oral corticosteroids in chronic asthma. Am J Respir Crit Care Med
25. Wenzel SE, Busse WW. Severe asthma: lessons from the severe asthma
research program. J Allergy Clin Immunol 2007;119:14–21.
26. American Thoracic Society. Proceedings of the ATS Workshop on
Refractory Asthma: current understanding, recommendations, and
unanswered questions. Am J Respir Crit Care Med 2000;162:2341–2351.
27. Ismaili N, Garabedian MJ. Modulation of glucocorticoid receptor
function via phosphorylation. Ann N Y Acad Sci 2004;1024:86–101.
28. Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene,
multiple proteins and diverse responses. Steroids 2005;70:407–417.
29. Goleva E, Kisich KO, Leung DY. A role for STAT5 in the pathogenesis of
IL-2–induced glucocorticoid resistance. J Immunol 2002;169:5934–5940.
30. Li LB, Goleva E, Hall CF, Ou LS, Leung DY. Superantigen-induced
corticosteroid resistance of human T cells occurs through activation of
the mitogen-activated protein kinase kinase/extracellular signal-regu-
lated kinase (MEK-ERK) pathway. J Allergy Clin Immunol 2004;114:
31. Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, Cato AC.
Glucocorticoids inhibit MAP kinase via increased expression and
decreased degradation of MKP-1. EMBO J 2001;20:7108–7116.
32. Zhao Q, Shepherd EG, Manson ME, Nelin LD, Sorokin A, Liu Y. The
role of mitogen-activated protein kinase phosphatase-1 in the re-
sponse of alveolar macrophages to lipopolysaccharide: attenuation of
proinflammatory cytokine biosynthesis via feedback control of p38.
J Biol Chem 2005;280:8101–8108.
33. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM.
Increased adipose tissue expression of tumor necrosis factor-a in
human obesity and insulin resistance. J Clin Invest 1995;95:2409–2415.
34. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The
expression of tumor necrosis factor in human adipose tissue: regula-
tion by obesity, weight loss, and relationship to lipoprotein lipase.
J Clin Invest 1995;95:2111–2119.
35. Krogh-Madsen R, Plomgaard P, Moller K, Mittendorfer B, Pedersen
BK. Influence of TNF-a and IL-6 infusions on insulin sensitivity and
expression of IL-18 in humans. Am J Physiol Endocrinol Metab 2006;
36. Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The
expression of TNF a by human muscle: relationship to insulin
resistance. J Clin Invest 1996;97:1111–1116.
37. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH,
Bradding P, Brightling CE, Wardlaw AJ, Pavord ID. Evidence of
a role of tumor necrosis factor a in refractory asthma. N Engl J Med
Sutherland, Goleva, Strand, et al.: Obesity, Asthma, and Steroid Resistance 687