A Common Pathway to Obesity and Allergic Asthma
Authors: Anne E. Dixon, Matthew E. Poynter
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

There is a strikingly high prevalence of obesity among individuals with asthma. Although about one-third of the U.S. population is obese, many recent studies of asthmatic populations report a prevalence of obesity of 50% or more in these individuals (1). Studies investigating the pathogenesis of asthma in obesity using animal models suggest that obesity causes an asthma-like phenotype through innate, non-Th2 pathways (2, 3). Indeed, there appears to be a phenotype of asthma, more common in women, with late-onset disease and low levels of markers of allergic inflammation (4). However, obesity is a risk factor for both atopic and nonatopic asthma (5). Many obese individuals have elevated serum eosinophils and high IgE levels (6), and although obesity is typically associated with low sputum eosinophil and low exhaled nitric oxide levels, there may be an abnormality of eosinophil trafficking in obesity, with elevated submucosal (but not sputum) eosinophil levels (7). As a consequence, at least two prominent phenotypes of asthma are now recognized in obesity: earlier-onset allergic disease and later-onset nonallergic disease (6, 8). Despite evidence to suggest contributions from mechanical, neurological, behavioral, and immunological factors, reasons for the association between obesity and allergic airway disease remain incompletely understood.

For many years, basic science and clinical researchers have been striving to understand whether there is something about allergic asthma that leads to the development of obesity (perhaps reduced physical activity or the adverse effects of medications), or conversely, whether there is something about obesity that leads to the development of allergic airway inflammation. In this issue of the Journal, Ahangari and colleagues (pp. 746–757) force us to rethink this question (9), as debating whether obesity or asthma comes first ignores a third possibility: that common pathways might promote both allergic airway disease and the development of visceral obesity.

Chitinase 3–like 1 (CHI3L1 in humans, Chi3l1 in mice) has been identified as an asthma susceptibility gene. Its protein product (Chi3l1; also known as YKL-40, BRP-39, and HC gp-39) is associated with risk for asthma and lung function impairment and is involved in the development of Th2 responses, allergic airway inflammation, and methacholine hyperresponsiveness (10). The current article suggests that Chi3l1 is also involved in the pathogenesis of obesity (9). Mice genetically deficient in Chi3l1 developed less visceral obesity and had smaller adipocytes, producing lower levels of cytokines, than wild-type controls. In contrast, transgenic overexpression of Chi3l1 from nonciliated airway epithelial cells induced adiposity. These data suggest that Chi3l1, a mediator promoting allergic airway inflammation, is also involved in the pathogenesis of obesity.

There are many pathways to the development of obesity in people; one key factor is a high-fat diet. The effects of a high-fat diet in this model were particularly salient to human disease: a high-fat diet increased the expression of Chi3l1 in both fat and lung and also increased allergic airway inflammation. Mice lacking Chi3l1 that were fed a high-fat diet had a muted response to antigen challenge, with fewer total inflammatory leukocytes and eosinophils in bronchoalveolar lavage, suggesting an interaction between a high-fat diet and allergic airway responses. Allergen challenge itself led to a small but significant increase in epididymal adipose tissue in mice fed a regular chow diet. These data suggest that a high-fat diet induces a mediator that promotes allergic airway inflammation in lung and that allergic airway inflammation by itself can increase obesity.

The article also implicates a signaling pathway that might mediate the effects of increased Chi3l1 expression. Expression of the histone deacetylase Sirtuin 1 (Sirt1), which regulates a number of transcription factors involved in inflammation and metabolism, was higher in the lungs and adipose tissue of wild-type than Chi3l1-deficient mice and increased in response to antigen challenge in both tissues. Pharmacologic blockade of Sirt1 in wild-type mice reduced allergic airway inflammation and Th2-type/proinflammatory cytokine expression, whereas these parameters and adiposity were enhanced in Chi3l1-deficient mice in which Sirt1 was inhibited. These data support the novel concept that signaling through Sirt1, via its effects on Chi3l1, is a pathogenic mediator of both allergic airway disease and obesity.

It is important to consider the limitations of extrapolating data from a mouse model of disease to humans. Recent work from Johnston and colleagues showed that airway allergic responses were diminished in some mouse models of obesity, yet enhanced in others (11, 12). The model of obesity and the genetic background of the mice modify the relationship between allergic airway disease and adiposity (13). In the current article, a high-fat diet increased allergic airway inflammation, whereas other investigators, using a different model, have reported that a high-fat diet decreases allergic airway inflammation (14, 15). Key data suggesting that the work by Ahangari and colleagues has direct relevance for human disease came from the inclusion of a case–control study showing that the human homolog of Chi3l1 (YKL-40) was increased in the serum of patients with persistent asthma and correlated with truncal obesity and low lung function (the latter only in obese patients with asthma). This provides important corroboration that this pathway may be important in the pathogenesis of human disease.

The functional effects of this pathway need to be better understood. Elevated serum YKL-40 correlated with low FEV1 in obese subjects with asthma, but the effects on airway reactivity are not known. Understanding the effect of the Chi3l1–Sirt1 pathway on airway reactivity in obesity will be important for understanding the functional implications of this pathway in the pathogenesis of disease.

Obesity and allergic asthma are complex processes in which many complementary and synergistic pathways contribute to clinical manifestations of disease. The current article suggests that a common factor can lead to the pathogenesis of both, as well as suggesting the appealing idea that intervention in the Sirt1–Chi3l1 pathway may simultaneously intervene in obesity and allergic asthma. Although pharmacologic approaches are attractive, the effect of dietary manipulation is of great interest. There is precedent to suggest a high-fat diet can affect airway inflammation: Wood and colleagues have reported that a high-fat meal can increase airway neutrophilic inflammation and decrease bronchodilator responsiveness in asthma (16). It will be of great interest to know whether dietary manipulation or other means of weight control could affect allergic asthma outcomes in obese people, analogous to the effects in mice from pharmacologic and genetic approaches targeting the Sirt1–Chi3l1 pathway.