Obesity: Changing Asthma in the 21st Century
Authors: Anne E. Dixon
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

The world is witnessing a major shift in human disease swept in by an unprecedented pandemic, obesity (1). This is changing the nature and presentation of health and disease. An obvious example is type II diabetes; once a disease of elderly overweight adults, this condition is now increasingly diagnosed in children. Lung health is no exception to this new era in human health. Obesity is a major risk factor for asthma. This has been reported in adults and children, in multiple demographic groups, and from countries around the world (2). Asthma in obesity tends to be characterized by poor control (3) and decreased responsiveness to standard controller therapies (4). The epidemiological evidence linking asthma and obesity is compelling.

While the epidemiological evidence linking asthma and obesity is impressive, the mechanistic link between these diseases is far from clear. Obesity has important effects on airway physiology (5), though the relationship between obesity and asthma is far more complex than might be anticipated from simple mass loading. Important insights into the relationship may be gained from recent work on mouse models of obesity and asthma, and also from understanding the changes in adipose tissue and metabolism that take place with obesity. Insights from these basic studies need to be translated into the context of the human airway, and the publication by Lugogo and colleagues in this issue of the Journal (pp. 404–411) represents an important step in this direction (6).

Work in mouse models of obesity and asthma has provided important clues into the potential nature of the relationship in humans (7). Airway reactivity is increased in obese mice, even without airway challenge (7). Adipokines such as leptin and adiponectin and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) appear to be involved in the pathogenesis of airway disease in obese mice (8). Studies in mice have provided a window into potential pathways that may link obesity and asthma in humans.

The last decade has seen major advances in our understanding of the pathophysiology of obesity. Adipose tissue is far from a passive energy storage depot; it is an important endocrine organ with major effects on immune function (9). In lean individuals, alternatively activated macrophages and eosinophils are found in adipose tissue. With obesity, macrophages in adipose tissue expand and take on a proinflammatory M1 phenotype elaborating cytokines such as IL-6, IL-1β, and TNF-α (10). Changes in macrophage function have been reported in organs other than adipose tissue: Kupfer cell function is altered in the liver, contributing to the development of steatohepatitis (10). These changes in immune function could have profound effects on the pathogenesis of airway disease if they also occur in the human lung.

Studies suggest that alveolar macrophage function may be altered in obesity. Mancuso and colleagues have shown that alveolar macrophage function is altered in leptin-deficient mice: macrophages from obese mice have impaired phagocytosis and abnormalities in leukotriene production (11, 12). This has important implications for host defense. Sutherland and colleagues, in the only previous study of alveolar macrophages isolated from overweight and obese human individuals with asthma, found impaired responsiveness to dexamethasone, of obvious relevance for the steroid resistance typical of obese asthma (13). In the article published in this issue of the Journal by Lugogo and colleagues, obese individuals with asthma were found to have altered response both to lipopolysaccharide and to lipopolysaccharide combined with leptin, when compared with obese control subjects, lean subjects with asthma, and lean control subjects. The investigators were careful to try and exclude the use of steroids, which could affect macrophage function, and although the levels of leptin used in the in vitro experiments were higher than that typically reported in obese individuals with asthma (250 ng/ml compared with 20–30 ng/ml in serum [14]), this study is important because it suggests that altered alveolar macrophage function and altered innate immunity are likely to be important features of asthma in obesity.

In addition to changes in macrophage function, the investigators made some noteworthy observations regarding bronchoalveolar lavage cytokines: TNF-α and leptin were particularly elevated in obese individuals with asthma. TNF-α has also been implicated in mouse studies of obesity and asthma (15). Given the therapeutic relevance of this pathway, this observation likely warrants further investigation. Leptin was also particularly elevated in bronchoalveolar lavage fluid of obese individuals with asthma. Shore and coworkers have previously shown that leptin infusion increases airway reactivity in lean mice; this is not related to increases in allergic airway inflammation, suggesting that leptin may be having effects in pathways quite distinct from those involved in allergic asthma (16). The observation that leptin was inversely related to lung function as measured by FEV1 is also intriguing, given reports that leptin is involved in lung development (17, 18) and may regulate fibroproliferative responses in the lung (19). Further studies evaluating the mechanistic relevance of elevated TNFα and leptin in airway disease in obese individuals with asthma are needed.

The study by Lugogo and colleagues has important implications for our understanding of obesity and asthma. Obesity perturbs immune function, and many of the circulating factors produced by adipose tissue may have effects on airway disease in obese individuals with asthma. It is likely that this leads to a quite different form of asthma than that typically associated with allergic airway disease. This likely explains the lack of response to standard therapies. Therapies developed based on insights gained from the study of lean allergic mouse models of asthma likely have limited relevance for asthma in obesity. Studies such as that of Lugogo and coworkers are essential if we are to understand airway disease in the 21st century.