help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1280
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
91/1/256    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vasudevan, A. R.
Right arrow Articles by Ballantyne, C. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vasudevan, A. R.
Right arrow Articles by Ballantyne, C. M.
Related Collections
Right arrow Obesity
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 256-261
Copyright © 2006 by The Endocrine Society

Eotaxin and Obesity

Abu R. Vasudevan, Huaizhu Wu, Antonios M. Xydakis, Peter H. Jones, E. O’Brian Smith, John F. Sweeney, David B. Corry and Christie M. Ballantyne

Division of Diabetes, Endocrinology, and Metabolism (A.R.V., A.M.X.), Section of Atherosclerosis and Lipoprotein Research (H.W., P.H.J., C.M.B.), and Section of Pulmonary and Critical Care Medicine (D.B.C.), Department of Medicine, Sections of Nutrition (E.O.S.) and Leukocyte Biology (C.M.B.), Department of Pediatrics, and Division of General Surgery, Department of Surgery (J.F.S.), Baylor College of Medicine, and Center for Cardiovascular Disease Prevention (P.H.J., C.M.B.), Methodist DeBakey Heart Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Christie M. Ballantyne, M.D., Baylor College of Medicine, 6565 Fannin, M.S. A-601, Houston, Texas 77030. E-mail: cmb{at}bcm.tmc.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Asthma and obesity incidence is increasing worldwide, and asthma is often more severe in the obese. Eotaxin, a CC chemokine, is important in extrinsic asthma, an inflammatory disorder.

Objective: Our objective was to examine the relation between eotaxin and obesity.

Design: We conducted a comparison study of eotaxin in mice fed high-fat vs. standard chow diet for 26 wk, in obese vs. lean humans, in obese humans before and after 4–6 wk of weight loss, and in sc vs. visceral adipose tissue from patients undergoing bariatric surgery.

Setting: Our clinical study occurred in an outpatient weight loss program.

Patients: Patients were obese adults with metabolic syndrome (n = 40) and nine morbidly obese bariatric surgery patients.

Intervention: Intervention was a very-low-calorie diet.

Main Outcome Measures: We assessed circulating eotaxin and eotaxin mRNA levels in adipose tissue.

Results: Serum eotaxin levels were significantly higher in obese mice, and adipose mRNA levels correlated positively with serum eotaxin levels. Adipose tissue explants from obese mice showed increased secretion of eotaxin compared with explants from lean mice. In obese patients, plasma eotaxin levels were significantly higher than in lean controls and significantly reduced after weight loss, and eotaxin mRNA levels were 4.7-fold higher in visceral than sc adipose tissue.

Conclusions: Circulating eotaxin and eotaxin mRNA levels in visceral adipose tissue were increased in obesity in mice and humans. Adipose tissue explants secrete eotaxin, and the stromal/vascular component of adipose tissue seems to be the predominant source of eotaxin. Diet-induced weight loss in humans led to reduction in plasma eotaxin levels, demonstrating that clinical interventions that target obesity can modulate systemic eotaxin levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESITY AND ASTHMA are two chronic inflammatory conditions affecting millions worldwide. The incidence and prevalence of obesity are increasing in the United States and elsewhere, with approximately one third of adult men and women overweight and more than 20% obese (1, 2). In the United States, between 1960 and 1994, the prevalence of obesity increased from 12.8 to 22.5% (3). Current evidence suggests a role for inflammatory mediators in the pathogenesis of obesity, insulin resistance syndrome, and type 2 diabetes mellitus (4). Increased fat mass, particularly with central obesity, leads to production of cytokines and chemokines, such as IL-6 (5), TNF-{alpha} (6), and monocyte chemoattractant protein-1 (7), a process that is under complex regulatory control involving autocrine, paracrine, and hormonal factors.

Likewise, the incidence, prevalence, and severity of adult asthma have been increasing in the United States. Between 1980 and 1994, the prevalence of self-reported asthma increased from 3.1 to 5.4% (8, 9). Collated data from the U.S. National Center for Health Statistics revealed that the prevalence of asthma in individuals aged 0–17 yr increased from 3.6% in 1980 to 6.2% in 1996 (10). Increased body mass index (BMI) has been associated with asthma symptoms (11, 12, 13, 14, 15, 16), airway hyperresponsiveness (17, 18, 19), and atopy (19, 20).

Eotaxin, a CC chemokine, has been shown to be a key chemotactic agent responsible for eosinophil-mediated bronchial inflammation in extrinsic or allergic asthma (21, 22, 23). Human eotaxin is an 8.3-kDa, 74-amino-acid residue, nonglycosylated polypeptide (24) secreted by endothelial cells (25), fibroblasts (26), macrophages (23, 25), ciliated and nonciliated bronchial epithelial cells (23, 25), smooth muscle cells (25), chondrocytes (25), and eosinophils (23). In this paper, we present new data on eotaxin expression in adipose tissue and in serum/plasma of mice and humans with diet-induced obesity and examine the effects of weight loss on eotaxin level.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Diet-induced obesity in mice

All animal studies were approved by the Animal Protocol Review Committee of Baylor College of Medicine. C57BL/6 mice (Harlan Sprague Dawley, Indianapolis, IN) were fed standard chow diet [4.5% (wt/wt) fat, 0.02% (wt/wt) cholesterol; PicoLab Rodent Chow 5053] after weaning until age 8 wk. Mice were then switched to a high-fat diet [21% (wt/wt) fat, 0.15% (wt/wt) cholesterol, 19.5% (wt/wt) casein; Harlan Teklad TD88137) and maintained on this diet for 26 wk. Lean control mice (C57BL/6) were fed standard chow diet until they were killed. All mice were housed in autoclaved microisolator cages on a 12-h day, 12-h night cycle. For each experiment, age- and sex-matched obese mice and lean controls were used.

Serum eotaxin was measured at 26 wk. At the time of the experiments, mice were weighed and then killed under anesthesia, and perigonadal (epididymal and periuterine fat pads in male and female mice, respectively) adipose tissue and other organs were collected by dissection, weighed, quickly frozen by immediate immersion in liquid nitrogen, and stored at –80 C for RNA isolation. For fractionation or explant culture, mouse adipose tissue, after collection, was put in Krebs-Ringer bicarbonate buffer and processed immediately.

Weight loss in humans

The clinical weight loss and bariatric surgery protocols were approved by the Institutional Review Board of Baylor College of Medicine, and written informed consent was obtained from each individual.

For the clinical weight loss program, obese individuals with the metabolic syndrome (23 women and 17 men), all of whom were enrolled in a medically supervised rapid weight loss program, were recruited over a 12-month period (September 2001 to September 2002). Entry criteria included age more than 18 yr and BMI at least 30 kg/m2; exclusion criteria included known eating disorder, cancer, use of lithium or corticosteroids, type 1 diabetes mellitus, active inflammatory bowel disease, active gout, liver disease, cardiovascular event within the past 3 months, endocrine causes of obesity, and pregnancy. Diuretic medications were discontinued before entering the program. Study participants did not receive any medication to lose weight or any other medication known to affect glucose tolerance, insulin secretion, or insulin sensitivity during the active weight loss period. Weight reduction was induced by a protein-sparing, very-low-calorie diet of approximately 600–800 kcal daily, consisting of meal replacement products (Nutrimed-Plus; Robard Corp., Mount Laurel, NJ; each serving contained 200 kcal, 6 g fat, 26 g protein, and 10 g carbohydrate) alone or in combination with lean beef, fish, or poultry. Daily protein intake was calculated as 1.5 g/kg of predetermined goal weight, and daily fluid intake was a minimum of 2 liters. Anthropometric measurements and laboratory tests were performed in subjects after an overnight fast. Biochemical measurements were performed at baseline and after 4–6 wk of active weight loss.

For comparison, we used 13 volunteers (seven women and six men) from our hospital staff as lean controls without the metabolic syndrome. None of them had diabetes mellitus, hypertension, asthma, or inflammatory bowel disease.

In addition, nine morbidly obese patients (eight women and one man) undergoing bariatric surgery provided visceral adipose tissue (VAT; perigastric omentum) and sc adipose tissue (SAT) samples at the time of surgery.

Laboratory methods

All biochemical measurements were performed on a Hitachi 911 auto-analyzer (Roche Diagnostics, Indianapolis, IN) using frozen plasma samples obtained by centrifugation of freshly drawn blood (3000 x g for 20 min at 4 C) and subsequent storage at –70 C. Serum and plasma eotaxin levels were measured using Quantikine ELISA kits (R&D Systems, Minneapolis, MN) according to manufacturer’s protocols. The limit of detection for this kit was less than 5 pg/ml, and the inter- and intraassay coefficients of variation were 8.4 and 3.4%, respectively.

RNA was isolated from murine and human adipose tissues and other murine organs using Trizol reagent (Invitrogen, Carlsbad, CA) according to the manufacturer’s protocol, and eotaxin mRNA levels were measured using RNase protection assay (PharMingen, San Diego, CA). The [{alpha}-32P]UTP-labeled RNase-protected probes were resolved on CastAway 6% precast polyacrylamide sequencing gels (Stratagene, La Jolla, CA) and quantified by autoradiography. The quantity of each mRNA species was determined by the intensity of the appropriately sized, protected probe fragment relative to that of housekeeping genes GAPDH and L32.

For mouse adipose tissue explant culture, adipose tissue was minced and incubated in DMEM/Ham’s F12 (Invitrogen, Carlsbad, CA) supplemented with 1% BSA, penicillin/streptomycin, and 10 µg/ml insulin, with or without 10 ng/ml recombinant murine TNF-{alpha} (R&D Systems) (3 ml medium per gram tissue) for 24 h at 37 C. After culture, the medium was collected and used for eotaxin assay using Quantikine ELISA kits (R&D Systems). The amount of eotaxin secreted by mouse adipose tissue was expressed as picograms per gram adipose tissue.

Mouse adipose tissue was fractionated into adipocytes and stromal/vascular (S/V) cells by collagenase digestion as described previously (27). Briefly, adipose tissue was minced and incubated with 840 U/g collagenase type I (Worthington Chemicals, Lakewood, NJ) in Krebs-Ringer bicarbonate buffer (3 ml/g adipose) containing 10 mM glucose and 4% BSA for 1 h at 37 C with gentle agitation. The digest was filtered through a 250-µm chiffon mesh, and the floating adipocytes were separated from S/V cells pelleted by centrifugation at 500 x g for 5 min. The separated adipocytes and S/V cells were washed once in PBS and used for total RNA isolation as described above.

For adipocyte differentiation in vitro, murine 3T3-L1 preadipocytes were cultured to confluence in DMEM supplemented with 10% calf serum. At 2 d after confluence (d 0), cells were stimulated with DMEM supplemented with 10% fetal bovine serum (FBS), 1 µM dexamethasone (Sigma Chemical Co., St. Louis, MO), 0.5 mM isobutylmethylxanthine (Sigma), and 1 µg/ml bovine insulin (Sigma). On d 2, the media were changed to DMEM supplemented with 10% FBS and 1 µg/ml insulin. From d 4, the cells were refed every other day with DMEM supplemented with 10% FBS. On d 8, more than 90% of cells were differentiated to adipocytes by morphology. Then both 3T3-L1 preadipocytes and adipocytes were incubated in DMEM with or without 10 ng/ml recombinant murine TNF-{alpha} (R&D Systems) for 24 h at 37 C. The cells were subsequently collected and dissolved in Trizol reagent (Invitrogen) for RNA isolation.

Statistical analysis

All data were analyzed with SPSS 12.0 software (SPSS, Inc., Chicago, IL) and presented as mean ± SE for mice and mean ± SD for humans unless otherwise indicated. Student’s t test was used for comparison of independent means and for pairwise comparisons; two-tailed tests were used for significance testing. Pearson correlation coefficients were computed to test correlations.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Mice

Compared with lean control mice, obese mice weighed more and had heavier perigonadal fat pads (both P < 0.001). Obese male mice were heavier than obese female mice (P < 0.001), but a corresponding weight difference by sex was not seen in lean control mice. Obese male and female mice did not differ significantly with respect to weight of perigonadal fat pads (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Diet-induced obesity in mice

 
Obese mice had significantly increased mRNA levels of eotaxin as assessed by RNase protection assay in adipose tissue in both males and females (Fig. 1AGo). Serum eotaxin levels assessed by ELISA were significantly higher in obese mice (Fig. 1BGo), and a positive correlation was demonstrated between adipose mRNA levels and serum protein levels of eotaxin (r2 = 0.6052; P < 0.05) (Fig. 1CGo). Additionally, we examined eotaxin mRNA levels in mouse liver, spleen, heart, and skeletal muscle. Eotaxin mRNA level was increased in skeletal muscle of obese females (relative intensity to GAPDH, 333 ± 7 in obese females vs. 200 ± 13 in lean females; P < 0.01; n = 3) and tended to be increased in skeletal muscle of obese males (relative intensity to GAPDH, 334 ± 43 in obese males vs. 250 ± 20 in lean males; P = 0.12; n = 4). Eotaxin mRNA level was undetectable in livers and spleens in both obese and lean mice. No difference was found in eotaxin mRNA levels in the heart between obese and lean mice (data not shown).



View larger version (14K):
[in this window]
[in a new window]
  		FIG. 1. A, Eotaxin mRNA levels in mouse adipose tissue detected by RNase protection assay. Levels of eotaxin mRNA normalized to levels of GAPDH are shown for male (n = 6 per group) and female (n = 3 per group) mice. *, P < 0.05 for obese mice (high-fat diet; shaded bars) vs. lean mice (normal diet; white bars). B, Eotaxin protein levels in mouse serum detected by ELISA. Eotaxin protein levels in mouse serum are shown for male and female mice (n = 6 per group). *, P < 0.05; **, P < 0.01 for obese mice (high-fat diet; shaded bars) vs. lean mice (normal diet; white bars). C, Correlation between adipose mRNA levels and serum protein levels of eotaxin in mice. Pearson’s correlation (r = 0.778; P = 0.0081) demonstrates a significant correlation between adipose eotaxin mRNA levels and serum eotaxin levels in mice.

 
To test whether the increased eotaxin mRNA level in obese mouse adipose tissue leads to enhanced eotaxin secretion, mouse adipose tissue explants were cultured ex vivo for 24 h. As shown in Fig. 2AGo, adipose tissue from obese mice secreted significantly increased levels of eotaxin into medium compared with that of lean mice during a 24-h period (P < 0.05; n = 4 males). We also found that stimulation with 10 ng/ml TNF-{alpha} did not significantly increase the secretion of eotaxin from adipose tissue of either obese or lean mice (Fig. 2AGo).



View larger version (13K):
[in this window]
[in a new window]
  		FIG. 2. A, Eotaxin levels secreted by mouse adipose tissue explant culture, with and without added recombinant murine TNF-{alpha}. Adipose tissue from obese mice secreted significantly increased levels of eotaxin into medium compared with adipose tissue from lean mice during 24 h (n = 4 males). *, P < 0.05 for high-fat diet (HF) vs. normal diet (ND). B, Eotaxin mRNA levels in mouse adipocytes and S/V cells. Eotaxin mRNA levels were higher in isolated S/V cells than in adipocytes (n = 4). *, P < 0.05.

 
To examine the cellular source of eotaxin in adipose tissue, mouse adipose tissue was fractionated into adipocytes and S/V cells, and eotaxin mRNA levels were detected by RNase protection assay. Consistent with a previous report (28), we also found that the fractionation procedure with collagenase digestion itself up-regulated mRNA levels of proinflammatory molecules in both adipocytes and S/V cells (data not shown). From our present data, we showed that the major source of eotaxin in mouse adipose tissue was from the S/V fraction (Fig. 2BGo). As a second approach to examine whether adipocytes produce eotaxin, 3T3-L1 preadipocytes were induced to adipocyte differentiation in vitro. It was found that both 3T3-L1 preadipocytes and adipocytes expressed very low mRNA levels of eotaxin (data not shown) in contrast to monocyte chemoattractant protein-1 mRNA levels as previously reported (7).

Humans

Obese individuals with the metabolic syndrome (BMI, 38.9 ± 6.3 kg/m2), as compared with lean controls (BMI, 22.4 ± 2.5 kg/m2), had significantly higher plasma levels of eotaxin (82.6 ± 31.6 vs. 44.5 ± 22.0 pg/ml, respectively; P = 0.004) (Table 2Go). Pairwise comparisons of plasma eotaxin levels before and after weight loss (mean ± SD weight loss, 8.0 ± 3.8 kg) showed a significant reduction in serum eotaxin levels (to 62.8 ± 25.3 pg/ml; P < 0.001) (Table 2Go).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Comparison of obese patients with the metabolic syndrome before and after weight loss and lean controls

 
Examination of tissue obtained at bariatric surgery from morbidly obese patients (age, 38.3 ± 5.1 yr; weight, 130.0 ± 28.5 kg; BMI, 49.4 ± 8.7 kg/m2) revealed that eotaxin mRNA levels were 4.7-fold higher in VAT (omentum) than in SAT (anterior abdominal wall) as detected by RNase protection assay (P = 0.008) (Fig. 3Go).



View larger version (34K):
[in this window]
[in a new window]
  		FIG. 3. Eotaxin mRNA levels in human adipose tissue detected by RNase protection assay. Average levels of eotaxin mRNA normalized to mRNA levels of GAPDH are shown for SAT and VAT (perigastric omentum) from obese individuals undergoing bariatric surgery (n = 9); *, P = 0.0077 for SAT vs. VAT. Shown below the bar graph are representative lanes of SAT (lanes 1–5) and VAT (lanes 6–10) from five individuals in corresponding sequence.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this report, we have shown that circulating levels of eotaxin in serum/plasma are increased in diet-induced obesity in both mice and humans. High levels of eotaxin mRNA were observed in perigonadal fat in mice and omental fat in humans. Cultured mouse adipose tissue explants from obese mice on a high-fat diet secreted nearly three times as much eotaxin per gram of adipose tissue compared with explants from lean mice on a chow diet, suggesting that the increased serum levels in obese mice may be secondary to the increased eotaxin expression in adipose tissue from obese mice. Diet-induced weight loss in humans led to a reduction in plasma levels of eotaxin, demonstrating that clinical interventions that target obesity can modulate systemic eotaxin levels. To our knowledge, these are the first data that demonstrate that eotaxin is a secretory product of adipose tissue and its expression is reversibly increased in obesity. Our experiments with fractionated adipose tissue showed higher eotaxin levels in S/V cells, and cultured 3T3-L1 preadipocytes and adipocytes had low levels of eotaxin mRNA. Several investigators have shown that obesity is associated with macrophage accumulation in adipose tissue, and weight loss improves the inflammatory profile of obese subjects by altering the expression of genes related to proinflammatory factors in the macrophage-rich S/V component of adipose tissue (29, 30, 31).

Eotaxin plays a key role in the pathogenesis of extrinsic asthma. Serum eotaxin levels have been demonstrated to correlate significantly with asthma diagnosis in 500 asthmatic individuals not on steroids (32). In a case-control study, plasma eotaxin levels were significantly higher in 46 patients with acute asthma symptoms and airflow obstruction (mean, 520 pg/ml) than in 133 subjects with stable asthma (350 pg/ml; range, 190–620 pg/ml; P = 0.0008) (33). Tateno et al. (34) showed that plasma eotaxin levels were highest in asthmatics who required both inhaled and systemic steroids. Thus, serum eotaxin levels in humans have been shown to be associated with the presence and severity of asthma. We hypothesize that increased eotaxin levels with obesity are one of the factors that lead to the increased frequency and severity of asthma in obese individuals.

Eotaxin and other allergy-associated chemokines play essential roles in the pathogenesis of allergic diseases. Although typically viewed as accessory molecules relevant to the effector phase of allergic diseases, increasing evidence indicates a primary role for T helper type 2 (Th2)-related cytokines in allergic disease. Ectopic expression of several cytokines in the airway epithelium of mice leads to pronounced allergic lung inflammation and airway obstruction as seen in asthma (35, 36, 37, 38), without the need for exposure to allergen. Moreover, ectopic expression of eotaxin alone in the gut of mice was sufficient to induce Th2 cell-dependent gut inflammation and airway hyperreactivity, the sine qua non of asthma (39). Together, these findings provide strong evidence that eotaxin and related molecules can act as immunological adjuvants that promote allergic responses, especially at mucosal sites. However, independent of their priming effects on allergic inflammatory cells, various cytokines can also act directly on the rodent lung to promote airway hyperresponsiveness (40, 41). Obese mice with a genetic deficiency in leptin have been shown to have greater ozone-induced airway hyperresponsiveness and higher concentration of eotaxin in bronchoalveolar flow after exposure to ozone compared with lean wild-type mice (42). Thus, elevated systemic levels of eotaxin derived from adipose tissue could contribute to the signs and symptoms of asthma by promoting allergic inflammation in the lung and possibly by directly altering the airway to become more hyperresponsive (Fig. 4Go).



View larger version (30K):
[in this window]
[in a new window]
  		FIG. 4. Ectopic eotaxin model. Ectopic expression of eotaxin and other cytokines/chemokines in adipose tissue induces Th2 cell-dependent inflammation in the lung. Eotaxin may influence homing of bone marrow-derived eosinophils to the lung directly or indirectly by increasing Th2-type cytokines. In addition, eotaxin and cytokines produced by adipose tissue may possibly directly influence airway hyperresponsiveness, thereby leading to an increased prevalence and severity of asthma symptoms in obese individuals.

 
A major limitation of our study is that only one patient in the weight loss group had a diagnosis of asthma, and therefore we do not have any data on the effects of weight loss on asthma and relationship to eotaxin. Weight loss with a similar dietary program in obese patients with asthma has been shown to improve lung function, symptoms, and health status in a randomized parallel-group comparison of a very-low-calorie diet vs. no intervention in 38 obese asthmatics (43). At the 14-wk follow-up (with an initial 8 wk of low calorie-beverage diet), the participants in the diet treatment group had lost a mean 14.5% of their pretreatment weight (vs. 0.3% for controls); at the 1-yr follow-up, the respective treatment groups had an 11.3% decrease and 2.2% increase in body weight. At the end of 14 wk and 1 yr, forced expiratory volume in 1 sec (percentage of predicted) and forced vital capacity (percentage of predicted) were improved with weight loss. The investigators suggested that the improvement might be due to beneficial effects of weight loss on pulmonary mechanics, improved gas exchange, and possibly a decreased tendency to suffer gastroesophageal reflux disease.

Based on the results of our study, an ectopic eotaxin axis may define the pathogenetic link between extrinsic asthma and obesity (Fig. 4Go). Obesity is an inflammatory state, and adipose tissue is a source of both proinflammatory cytokines such as TNF-{alpha}, IL-1, and IL-6, which have been shown to be increased in the inflammatory response and asthma (6, 44, 45, 46), and chemokines. The weight loss-mediated decrease in fat mass, particularly VAT mass, with concomitant reductions in leukocytes in VAT, may lead to a diminished translocation of adipocytokines/chemokines such as eotaxin to potential sites of inflammation, thereby contributing to amelioration of asthma symptoms in susceptible individuals. Elucidation of these molecular mechanisms that link obesity to asthma may pave the way for novel therapies in individuals with these conditions.


   Acknowledgments
 
We acknowledge Kerrie Jara for editorial assistance.


   Footnotes
 
This work was supported by grants from the American Diabetes Association, the Methodist Research Hospital Foundation, and the Women’s Fund. The lipid laboratory was supported by donations from George and Cynthia Mitchell, Nijad and Zeina Fares, and Jeffrey and Wendy Hines.

First Published Online November 1, 2005

Abbreviations: BMI, Body mass index; FBS, fetal bovine serum; SAT, sc adipose tissue; S/V, stromal/vascular; Th2, T helper type 2; VAT, visceral adipose tissue.

Received June 8, 2005.

Accepted October 26, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. American Heart Association 2005 Heart disease and stroke statistics–2005 update. Dallas: American Heart Association
  2. Flegal KM, Carroll MD, Ogden CL, Johnson CL 2002 Prevalence and trends in obesity among US adults, 1999–2000. JAMA 288:1723–1727[Abstract/Free Full Text]
  3. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL 1998 Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord 22:39–47[CrossRef][Medline]
  4. Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G 1999 Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 353:1649–1652[CrossRef][Medline]
  5. Fried SK, Bunkin DA, Greenberg AS 1998 Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83:847–850[Abstract/Free Full Text]
  6. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM 1995 Increased adipose tissue expression of tumor necrosis factor-{alpha} in human obesity and insulin resistance. J Clin Invest 95:2409–2415[Medline]
  7. Sartipy P, Loskutoff DJ 2003 Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270[Abstract/Free Full Text]
  8. Mannino DM, Homa DM, Pertowski CA, Ashizawa A, Nixon LL, Johnson CA, Ball LB, Jack E, Kang DS 1998 Surveillance for asthma–United States, 1960–1995. MMWR CDC Surveill Summ 47:1–27[Medline]
  9. Anderson HR 1989 Is the prevalence of asthma changing? Arch Dis Child 64:172–175[Medline]
  10. Akinbami LJ, Schoendorf KC 2002 Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics 110:315–322[Abstract/Free Full Text]
  11. Figueroa-Munoz JI, Chinn S, Rona RJ 2001 Association between obesity and asthma in 4–11 year old children in the UK. Thorax 56:133–137[Abstract/Free Full Text]
  12. Schachter LM, Salome CM, Peat JK, Woolcock AJ 2001 Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness. Thorax 56:4–8[Abstract/Free Full Text]
  13. Shaheen SO, Sterne JA, Montgomery SM, Azima H 1999 Birth weight, body mass index and asthma in young adults. Thorax 54:396–402[Abstract/Free Full Text]
  14. Kaplan BA, Brush G, Mascie-Taylor CG 1987 The relationship of childhood asthma and wheezy bronchitis with height, weight and body mass index. Hum Biol 59:921–931[Medline]
  15. Luder E, Melnik TA, DiMaio M 1998 Association of being overweight with greater asthma symptoms in inner city black and Hispanic children. J Pediatr 132:699–703[CrossRef][Medline]
  16. Belamarich PF, Luder E, Kattan M, Mitchell H, Islam S, Lynn H, Crain EF 2000 Do obese inner-city children with asthma have more symptoms than nonobese children with asthma? Pediatrics 106:1436–1441[Abstract/Free Full Text]
  17. Kanner RE, Connett JE, Altose MD, Buist AS, Lee WW, Tashkin DP, Wise RA 1994 Gender difference in airway hyperresponsiveness in smokers with mild COPD. The Lung Health Study. Am J Respir Crit Care Med 150:956–961[Abstract]
  18. Kaplan TA, Montana E 1993 Exercise-induced bronchospasm in nonasthmatic obese children. Clin Pediatr (Phila) 32:220–225[Abstract/Free Full Text]
  19. Huang SL, Shiao G, Chou P 1999 Association between body mass index and allergy in teenage girls in Taiwan. Clin Exp Allergy 29:323–329[CrossRef][Medline]
  20. Xu B, Jarvelin MR, Pekkanen J 2000 Body build and atopy. J Allergy Clin Immunol 105:393–394[CrossRef][Medline]
  21. Griffiths-Johnson DA, Collins PD, Rossi AG, Jose PJ, Williams TJ 1993 The chemokine, eotaxin, activates guinea-pig eosinophils in vitro and causes their accumulation into the lung in vivo. Biochem Biophys Res Commun 197:1167–1172[CrossRef][Medline]
  22. Rothenberg ME, Luster AD, Leder P 1995 Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cells and in interleukin 4-induced tumor suppression. Proc Natl Acad Sci USA 92:8960–8964[Abstract/Free Full Text]
  23. Ponath PD, Qin S, Ringler DJ, Clark-Lewis I, Wang J, Kassam N, Smith H, Shi X, Gonzalo JA, Newman W, Gutierrez-Ramos JC, Mackay CR 1996 Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest 97:604–612[Medline]
  24. Kitaura M, Nakajima T, Imai T, Harada S, Combadiere C, Tiffany HL, Murphy PM, Yoshie O 1996 Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. J Biol Chem 271:7725–7730[Abstract/Free Full Text]
  25. Li D, Wang D, Griffiths-Johnson DA, Wells TN, Williams TJ, Jose PJ, Jeffery PK 1997 Eotaxin protein and gene expression in guinea-pig lungs: constitutive expression and upregulation after allergen challenge. Eur Respir J 10:1946–1954[Abstract]
  26. Bartels J, Schluter C, Richter E, Noso N, Kulke R, Christophers E, Schroder JM 1996 Human dermal fibroblasts express eotaxin: molecular cloning, mRNA expression, and identification of eotaxin sequence variants. Biochem Biophys Res Commun 225:1045–1051[CrossRef][Medline]
  27. Robker RL, Collins RG, Beaudet AL, Mersmann HJ, Smith CW 2004 Leukocyte migration in adipose tissue of mice null for ICAM-1 and Mac-1 adhesion receptors. Obes Res 12:936–940[Medline]
  28. Ruan H, Zarnowski MJ, Cushman SW, Lodish HF 2003 Standard isolation of primary adipose cells from mouse epididymal fat pads induces inflammatory mediators and down-regulates adipocyte genes. J Biol Chem 278:47585–47593[Abstract/Free Full Text]
  29. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW 2003 Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808[CrossRef][Medline]
  30. Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A 2004 From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 53:1285–1292[Abstract/Free Full Text]
  31. Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, Sicard A, Rome S, Benis A, Zucker JD, Vidal H, Laville M, Barsh GS, Basdevant A, Stich V, Cancello R, Langin D 2004 Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J 18:1657–1669[Abstract/Free Full Text]
  32. Nakamura H, Weiss ST, Israel E, Luster AD, Drazen JM, Lilly CM 1999 Eotaxin and impaired lung function in asthma. Am J Respir Crit Care Med 160:1952–1956[Abstract/Free Full Text]
  33. Lilly CM, Woodruff PG, Camargo Jr CA, Nakamura H, Drazen JM, Nadel ES, Hanrahan JP 1999 Elevated plasma eotaxin levels in patients with acute asthma. J Allergy Clin Immunol 104:786–790[CrossRef][Medline]
  34. Tateno H, Nakamura H, Minematsu N, Nakajima T, Takahashi S, Nakamura M, Fukunaga K, Asano K, Lilly CM, Yamaguchi K 2004 Plasma eotaxin level and severity of asthma treated with corticosteroid. Respir Med 98:782–790[CrossRef][Medline]
  35. Lee JJ, McGarry MP, Farmer SC, Denzler KL, Larson KA, Carrigan PE, Brenneise IE, Horton MA, Haczku A, Gelfand EW, Leikauf GD, Lee NA 1997 Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J Exp Med 185:2143–2156[Abstract/Free Full Text]
  36. Rankin JA, Picarella DE, Geba GP, Temann UA, Prasad B, DiCosmo B, Tarallo A, Stripp B, Whitsett J, Flavell RA 1996 Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci USA 93:7821–7825[Abstract/Free Full Text]
  37. Mould AW, Ramsay AJ, Matthaei KI, Young IG, Rothenberg ME, Foster PS 2000 The effect of IL-5 and eotaxin expression in the lung on eosinophil trafficking and degranulation and the induction of bronchial hyperreactivity. J Immunol 164:2142–2150[Abstract/Free Full Text]
  38. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA 1999 Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 103:779–788[Medline]
  39. Forbes E, Smart VE, D’Aprile A, Henry P, Yang M, Matthaei KI, Rothenberg ME, Foster PS, Hogan SP 2004 T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice. Gastroenterology 127:105–118
  40. Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, Elias JA, Sheppard D, Erle DJ 2002 Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med 8:885–889[Medline]
  41. Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB 1998 Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282:2261–2263[Abstract/Free Full Text]
  42. Shore SA, Rivera-Sanchez YM, Schwartzman IN, Johnston RA 2003 Responses to ozone are increased in obese mice. J Appl Physiol 95:938–945[Abstract/Free Full Text]
  43. Stenius-Aarniala B, Poussa T, Kvarnstrom J, Gronlund EL, Ylikahri M, Mustajoki P 2000 Immediate and long term effects of weight reduction in obese people with asthma: randomised controlled study. BMJ 320:827–832[Abstract/Free Full Text]
  44. Bunout D, Munoz C, Lopez M, de la Maza MP, Schlesinger L, Hirsch S, Pettermann M 1996 Interleukin 1 and tumor necrosis factor in obese alcoholics compared with normal-weight patients. Am J Clin Nutr 63:373–376[Abstract/Free Full Text]
  45. Virchow Jr JC, Kroegel C, Walker C, Matthys H 1996 Inflammatory determinants of asthma severity: mediator and cellular changes in bronchoalveolar lavage fluid of patients with severe asthma. J Allergy Clin Immunol 98:S27–S33
  46. Bastard JP, Jardel C, Delattre J, Hainque B, Bruckert E, Oberlin F 1999 Evidence for a link between adipose tissue interleukin-6 content and serum C-reactive protein concentrations in obese subjects. Circulation 99:2221–2222[Medline]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
K M Choi, J H Kim, G J Cho, S H Baik, H S Park, and S M Kim
Effect of exercise training on plasma visfatin and eotaxin levels
Eur. J. Endocrinol., October 1, 2007; 157(4): 437 - 442.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
R. A. Johnston, M. Zhu, Y. M. Rivera-Sanchez, F. L. Lu, T. A. Theman, L. Flynt, and S. A. Shore
Allergic Airway Responses in Obese Mice
Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 650 - 658.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
H. Sandig, J. McDonald, J. Gilmour, M. Arno, T. H. Lee, and D. J. Cousins
Human Th2 cells selectively express the orexigenic peptide, pro-melanin-concentrating hormone
PNAS, July 24, 2007; 104(30): 12440 - 12444.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
H. Wu, S. Ghosh, X. D. Perrard, L. Feng, G. E. Garcia, J. L. Perrard, J. F. Sweeney, L. E. Peterson, L. Chan, C. W. Smith, et al.
T-Cell Accumulation and Regulated on Activation, Normal T Cell Expressed and Secreted Upregulation in Adipose Tissue in Obesity
Circulation, February 27, 2007; 115(8): 1029 - 1038.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
S. A. Shore
Obesity and asthma: lessons from animal models
J Appl Physiol, February 1, 2007; 102(2): 516 - 528.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. A. Beuther, S. T. Weiss, and E. R. Sutherland
Obesity and Asthma
Am. J. Respir. Crit. Care Med., July 15, 2006; 174(2): 112 - 119.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
C. Herder, H. Hauner, B. Haastert, K. Rohrig, W. Koenig, H. Kolb, S. Muller-Scholze, B. Thorand, R. Holle, and W. Rathmann
Hypoadiponectinemia and Proinflammatory State: Two Sides of the Same Coin?: Results From the Cooperative Health Research in the Region of Augsburg Survey 4 (KORA S4)
Diabetes Care, July 1, 2006; 29(7): 1626 - 1631.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
91/1/256    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vasudevan, A. R.
Right arrow Articles by Ballantyne, C. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vasudevan, A. R.
Right arrow Articles by Ballantyne, C. M.
Related Collections
Right arrow Obesity

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals