Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

Abstract

The majority of patients with severe or difficult-to-control asthma in the United States are obese. Epidemiological studies have clearly established that obese patients tend to have worse asthma control and increased hospitalizations and do not respond to standard controller therapy as well as lean patients with asthma. Less clear are the mechanistic underpinnings for the striking clinical differences between lean and obese patients with asthma. Because obesity is principally a disorder of metabolism and energy regulation, processes fundamental to the function of every cell and system within the body, it is not surprising that it affects the respiratory system; it is perhaps surprising that it has taken so long to appreciate how dysfunctional metabolism and energy regulation lead to severe airway disease. Although early investigations focused on identifying a common factor in obesity that could promote airway disease, an appreciation has emerged that the asthma of obesity is a manifestation of multiple anomalies related to obesity affecting all the different pathways that cause asthma, and likely also to de novo airway dysfunction. Consequently, all the phenotypes of asthma currently recognized in lean patients (which are profoundly modified by obesity), as well as those unique to one's obesity endotype, likely contribute to obese asthma in a particular individual. This perspective reviews what we have learned from clinical studies and animal models about the phenotypes of asthma in obesity, which show how specific aspects of obesity and altered metabolism might lead to de novo airway disease and profoundly modify existing airway disease.

Glucagon-like peptide 1: A potential anti-inflammatory pathway in obesity-related asthma

“…Obesity and metabolic syndrome are associated with an increased risk of coincident asthma and may represent distinct asthma phenotypes (Brumpton et al, 2013; Camargo et al, 1999). Some have traditional Th2-high asthma, but others have an increasingly recognized Th2-low asthma that tends to be more common in women, later in onset, and difficult to treat (Dixon and Poynter, 2016). …”

Gene Coexpression Networks in Whole Blood Implicate Multiple Interrelated Molecular Pathways in Obesity in People with Asthma

“…In this work, we used whole blood gene expression profiling to characterize the biology of a form of asthma in people with obesity known as “asthma complicated by obesity” (i.e., cases in which asthma preceded the development of obesity). Among 514 subjects who were diagnosed with asthma as children, we identified three coexpression network modules jointly associated with adult obesity.…”

“…Obesity is associated with a significantly higher risk for developing asthma, worse asthma symptoms, poor asthma control, and greater resistance to standard asthma therapies . A recent review postulated at least three (likely four) endotypes of asthma in people with obesity , distinguished by the relative timings of each disease’s onset (onset during childhood versus adulthood) and by their underlying pathophysiologies (differing effects of obesity on airway structure, function, sensitivity, and/or inflammation). A more complete understanding of the complex molecular relationships between obesity and asthma would drive the development of specific and effective preventive and therapeutic strategies for this overlap syndrome.…”

Innate lymphoid cells at the interface between obesity and asthma

“…Foremost, obesity contributes to asthma exacerbation in children in whom the disease is mostly allergic. However, the underlying mechanisms remain poorly understood . Mechanical effects linked to overweight and adipose tissue (AT) accumulation, as well as obesity‐associated inflammation, have been implicated.…”

“…However, the underlying mechanisms remain poorly understood. 18,19 Mechanical effects linked to overweight and adipose tissue (AT) accumulation, as well as obesity-associated inflammation, have been implicated. For example, It has been shown that breathing at low lung volumes 20 as well as augmented airway wall thickness, 21 increases airway reactivity.…”