Editorials

Adiponectin: The Link Between Obesity and Asthma in Women?

The study by Sood and colleagues in this issue of the Journal (pp. 4147) provides further insight into the association between obesity and asthma (1). Both obesity and asthma have increased in prevalence in recent decades, and asthma risk is increased by 50% in the overweight and obese (2). Obesity appears to have a causal role in asthma, as prospective studies have reported that obesity precedes asthma onset and weight gain is associated with asthma onset (3). The mechanisms linking asthma and obesity are not well understood, with mechanical, anatomical, and inammatory causes being proposed. Sood and coworkers examine adiponectin as a potential link. Adiponectin is a hormone secreted by adipose tissue. Other adipose tissuederived hormones include leptin and resistin. Each of these hormones is biologically active, and receptors to these molecules are widely distributed throughout the body, including the lungs. As circulating levels of these hormones are largely determined by adipose tissue mass, their biochemical and functional effects are magnied in the obese. Leptin and resistin are increased in obesity and have proinammatory effects, including activation of nuclear factor-kB (NF-kB) (4, 5), up-regulation of tumor necrosis factor a (TNFa) levels (6, 7), and enhancement of neutrophilic airway inammation (8, 9). Adiponectin, on the other hand, generally acts as an antiinammatory hormone and is reduced by obesity (10), most likely due to macrophage release of TNFa and IL-6, which inhibits adipocyte production of adiponectin (11). Adiponectin negatively regulates toll-like receptor signaling pathways (12), inhibits NF-kB activity (12), suppresses cytokine production, including IL-6 and TNFa (13), and was shown to reduce both airway hyperresponsiveness and airway neutrophilia in an animal model (14). As the balance between adiponectin and leptin is disturbed in the obese, this may be causing an NF-kBdriven increase in neutrophilic airway inammation. This is supported by our recent report of enhanced neutrophilic airway inammation in obese subjects with asthma (15) and may be contributing to the increased asthma risk in women with low adiponectin levels in the study by Sood and colleagues. Cross-sectional, observational studies in humans show that levels of adipose tissuederived hormones are altered in asthma. Leptin (16) and resistin (17) levels are increased in subjects with asthma, independent of body mass index. Conversely, adiponectin levels have been shown to be reduced in asthma in some studies (18) and reduced in subjects with low lung function (19). Interestingly, two studies have reported that these relationships only occur in women (16, 18). This concurs with some studies that have suggested that the relationship between obesity and asthma is specic to women (3). The mechanism behind this sex effect is unknown. It has been hypothesized that because women have a higher proportion of body fat, the effect of adipose tissue may be more pronounced (20). In one study, in which percentage body fat was measured to provide a measure of obesity superior to body mass index, body fat was associated with both asthma incidence and airow obstruction (20). Alternatively, as obese women have increased levels of estrogen, which is an independent risk factor for asthma, the effect may be due to
Am J Respir Crit Care Med Vol 186, Iss. 1, pp 110, Jul 1, 2012 Internet address: www.atsjournals.org

Figure 1. Modiable risk factors for asthma in women. Obesity and smoking can modify the clinical expression of asthma in women, via amplication of systemic inammatory pathways. AHR airway hyperresponsiveness; ERV expiratory reserve volume; TNFa tumor necrosis factor a.

an interaction between estrogen, adipose tissuederived hormones, and asthma (21). The current study by Sood and coworkers reports that in adult women, the development of new-onset asthma over a 5-year period was negatively associated with total serum adiponectin levels, as measured by radioimmunoassay using a polyclonal antibody. The participants were a subset of a longitudinal cohort study that was designed to evaluate the development of cardiac disease. The univariate analyses show the cluster of disparities that is associated with adult-onset asthma in women, namely smoking, low socioeconomic status, and now, low serum adiponectin. Smoking added to the effect of low adiponectin. This is an intriguing result. It may demonstrate the additive effect of two triggers of the IL-6 pathway, or identify a mechanistic interaction between smoking and low serum adiponectin levels (Figure 1). An important next step in this area is to examine the effect of interventions that reduce adipose tissue mass on adiponectin levels, to establish causality. To date, interventional studies in humans are limited. A recent study in asthmatic adolescents provides evidence of a causal relationship between asthma and adiponectin. Following a 12-month diet and exercise weight loss intervention, mean body fat mass was reduced from 48 6 5% to 38 6 9%, lung function (%predicted FEV1 and FVC) improved, symptoms (cough and wheeze) improved, adiponectin levels increased, and leptin levels decreased. Furthermore, there was a correlation between improvement in lung function and adiponectin levels (22). Although this very successful intervention did not present analysis by sex, interestingly, 75% of participants were female. In summary, sex has an important impact on lung disease that is well recognized in asthma. Menarche, menstruation, pregnancy, and menopause can all modify the clinical expression of asthma in women. Obesity can now be added to this list. Together with smoking, they represent important modiable risk factors for asthma in women. Low serum adiponectin may mark those women at risk of this adverse effect. Although further work is needed to understand the mechanism of the interaction between sex and asthma, these observations highlight the need to analyze data by sex, to avoid missing key effects. Adipose tissuederived hormones may prove to be an important factor in managing obese asthma, particularly in women.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 186

2012

Author disclosures are available with the text of this article at www.atsjournals.org.

Lisa G. Wood, B.Sc. (Hons.), Ph.D. Centre for Asthma and Respiratory Diseases University of Newcastle Newcastle, New South Wales, Australia Peter G. Gibson, M.B.B.S. (Hons.) Centre for Asthma and Respiratory Diseases University of Newcastle Newcastle, New South Wales, Australia and Hunter Medical Research Institute John Hunter Hospital Newcastle, New South Wales, Australia
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Copyright 2012 by the American Thoracic Society DOI: 10.1164/rccm.201204-0744ED

The Search for Diagnostic Markers in Sepsis

Many Miles Yet to Go
Join bedside rounds in any ICU around the world, and within a few minutes, you are nearly guaranteed to hear a vigorous discussion on whether or not a particular patient has sepsis. Despite the many advances in medicine and medical technology over the past decades, early and accurate identication of many of the syndromes we treat most commonly in the ICUfor example, sepsis and acute lung injuryremains a challenge, even for skilled and experienced clinicians. In this regard, cardiologists and oncologists are well ahead of intensivists, with reasonably accurate diagnostic biomarkers for some of their most commonly treated conditions (troponin for acute myocardial infarction, brain natriuretic peptide for
Supported by National Institutes of Health grants HL090833 and HL110969 (C.S.C.), the Flight Attendant Medical Research Institute (C.S.C.), and the Swiss National Foundation for Scientic Research (grant #141143 to J.P.).

congestive heart failure, and prostate-specic antigen for prostate cancer). Intensivists are naturally at some disadvantage due to the heterogenous pathophysiology of the syndromes we encounter, but the potential value of biomarker-guided diagnosis for sepsis is high. Much as early intervention is critical for the treatment of myocardial infarction, there is clear evidence that early treatment of sepsis with appropriate uid management and antibiotics has major benecial effects on clinical outcomes (1). Likewise, ever-increasing rates of antibiotic resistance dictate that antibiotics be rapidly discontinued in critically ill patients who prove not to be infected. Thus, despite the challenges, the search for accurate early diagnostic markers for sepsis should continue. The statistical requirements for an accurate diagnostic biomarker are high, and as such have been difcult to meet. Many markers that have strong associations with the outcome or disease of interest nevertheless fail to discriminate accurately between