The diverse effects of obesity on lung health and disease are increasingly being teased apart, with researchers honing in on the impact of metabolic dysfunction, circulating inflammatory factors produced by adipose tissue, lipid handling, and other factors – in addition to body mass index – that are associated with the obese state.
"The bird's eye view is that obesity completely changes lung health. It's something we've only recently begun to appreciate," said Anne E. Dixon, MA, BM, BCh, director of the Vermont Lung Center at the University of Vermont, Burlington, who is focused on the research field of obesity and lung disease.
Structural, mechanical effects of obesity on lung function are better known and appreciated. Accumulation of fat in the mediastinum and abdominal and thoracic cavities causes reductions in lung volume, in functional residual capacity, and in the compliance of the lungs, chest wall, and entire respiratory system, for instance.
Yet obesity is more than a state of increased BMI, and "what we've begun to understand is that [its impact on the lungs and respiratory health] is much more complicated than just a mechanical problem," said Dixon, also director of pulmonary and critical care medicine at the University of Vermont Medical Center and professor of medicine at the medical college.
With obesity, adipose tissue changes not only in quantity, but in function, producing proinflammatory cytokines and hormones – such as leptin, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 – that can have direct effects on the lung. Insulin resistance, which is common with obesity, is also seemingly deleterious. And obesity-associated changes in immune function, lipid handling, diet, and the gut microbiome may also impact lung health and disease, she said.
Dixon, who wrote about these changes in a 2018 review article in the journal CHEST and another 2019 piece in Expert Review of Respiratory Medicine, has developed a research program focused on obesity and lung disease and has edited a book and organized international conferences on the topic. (CHEST 2018;153:702-9 and Exper Rev Respir Med. 2018;12:755-67.)
"The more I do, the more I realize that there are multiple obesity-associated changes involved, and that [our current high level of] obesity is like a huge population-level natural experiment ... on lung health," she told this news organization.
Associations between lung disease and the metabolic and other disturbances of obesity are most established in asthma research and have taken hold in the realm of sleep-disordered breathing. But as the prevalence of obesity continues to grow, its role in other lung diseases such as chronic obstructive pulmonary disorder (COPD) and, most recently, pulmonary arterial hypertension (PAH), is getting attention in academia.
And certainly, COVID-19 has highlighted an "urgent need" to better understand how obesity increases susceptibility to severe viral infections, Dixon added.
Here are some glimpses into current thinking and some examples of research that may have preventive and therapeutic implications in the future:
OSA and OHS
"With sleep apnea we tend to focus on anatomic considerations, but there may be relationships or interactions between obesity and neuromuscular function and neuroventilatory control," Susheel P. Patil, MD, PhD, director of the sleep medicine program for University Hospitals and assistant professor at Case Western Reserve University, Cleveland, said in an interview.
Some studies suggest, for instance, that TNF-alpha can increase obstructive sleep apnea (OSA) susceptibility and severity through its neuroventilatory modulating properties during sleep. And the potential for additional proinflammatory cytokines produced by adipose tissue to similarly affect upper airway neuroventilatory control is an "intriguing line" of inquiry for researchers in the sleep apnea space, he said.
Leptin is of interest particularly in obesity hypoventilation syndrome (OHS), which is characterized by chronic daytime hypercapnia. Best known as a satiety hormone, leptin is produced by adipose tissue and suppresses appetite at the central nervous system level. But it has long been known that leptin also affects ventilation and the control of breathing.
When transported across the blood-brain barrier, leptin increases the hypercapnic ventilatory response, Babak Mokhlesi, MD, MSc, codirector of the Rush Lung Center and chief of pulmonary, critical care, and sleep medicine at Rush University Medical Center in Chicago, said in an interview.
Research suggests that patients with OHS may have resistance to leptin at the central nervous system level – with leptin not reaching the sites of ventilatory control. This is a "prevailing theory" and could explain why these patients "do not augment their ventilation to maintain homeostasis, normal levels of CO2," Mokhlesi said.
"Why some patients with severe obesity develop CO2 retention while others do not is not fully understood," he said, noting that patients with OHS can normalize their CO2 quickly when instructed to take deep breaths. "What we know is that the centers in the brain responsible for augmenting ventilation when CO2 goes up are somehow blunted."
In a study of obese mice led by Vsevolod Y. Polotsky, MD, PhD, of Johns Hopkins University, Baltimore – and highlighted by Mokhlesi as an example of important, recent research – leptin delivered intranasally alleviated hypoventilation (and upper-airway obstruction), while intraperitoneally administered leptin did not, seemingly overcoming "central leptin deficiency." (Am J Respir Crit Care Med. 2019;199:773-83).
"This proved that there is some level of resistance in this animal model ... and has potential for therapeutics in the future," Mokhlesi said.
Understanding the role of insulin resistance in OSA is another research focus. Some data suggest that insulin resistance, which is more common in obesity, is more prevalent in populations with OSA, Patil said. Researchers have discussed a bidirectional relationship for years, but it's likely that insulin resistance is a precursor, he said.
In a mechanistic study published in 2016, Patil and his coinvestigators found that obese individuals with insulin resistance but without frank diabetes or sleep apnea demonstrated preclinical elevations in pharyngeal collapsibility during sleep. The findings suggest that insulin resistance could play a causal role in OSA pathogenesis by "generating requisite elevations in pharyngeal collapsibility," they wrote (Eur. Respir J. 2016;47:1718-26).
More recently, Patil noted in the interview, there is increasing appreciation in academia that the type of fat may be important to predicting OSA. "Visceral fat has a completely different cytokine-secretion profile than subcutaneous fat ... it is the more metabolically active fat that may secondarily impact upper airway function though a neuroinflammatory mechanism," he said. "That is one of the working hypotheses today."
Research has so roundly suggested that metabolic dysfunction contributes to severe, poorly controlled asthma that there's recent and growing interest in targeting metabolic dysfunction as part of the treatment of obese asthma, said Dixon, whose own research in obesity and lung disease has focused on asthma.
Data from animal models and some epidemiologic studies have suggested that drugs used to treat type 2 diabetes mellitus, such as glucagon-like peptide receptor-1 (GLPR-1) agonists and metformin, may help control asthma. In one recent study – cited by Dixon in a 2022 review of obesity and asthma – people with obesity and asthma who were prescribed GLPR-1 agonists for diabetes had fewer asthma exacerbations compared with those who took other medications for diabetes (Semin Respir Crit Care Med. 2022 Feb 17. doi: 10.1055/s-0042-1742384).
There is also research interest in targeting the pro-inflammatory adipokine interleukin 6 (IL-6), since increased circulating levels of IL-6 correlate with asthma severity, and in addressing oxidative stress in asthma through treatment with a mitochondrially targeted antioxidant, she said. Oxidative stress is increased in the airways of people with obesity, and researchers believe it may contribute to the pathophysiology of obese asthma through effects on airway nitric oxide levels.
(Her own research work at the University of Vermont has found associations between poor asthma control and high levels of leptin, and similar associations involving low levels of adiponectin, an anti-inflammatory adipokine that has been shown to downregulate eosinophil recruitment in the airways.)
Weight loss has been shown in mostly small, single-center studies to improve asthma control, but short of weight loss, researchers are also investigating the role of poor dietary quality. Thus far, data suggest that it's the composition of the diet, and not just its contribution to weight gain, that could be impactful, Dixon said.
More basic research questions cited by Dixon include the extent to which adipose tissue inflammation causes inflammation in the lungs. "It's a little unclear whether all the metabolic dysfunction associated with poor asthma control is causing inflammation in the lungs," she said, though "we've done some work here that shows mediators produced by the adipose tissue could be impacting production of inflammatory mediators by the airway epithelium."
Overall, she said, "the big questions [in asthma] are, how does adipose tissue affect the airway? Is it through direct effects? Through effects on the immune system? And obesity is affected by diet and the gut microbiome – how can these be [impacting] the airway?"
Obesity "is associated with so many changes – the gut, the immune system, and metabolic dysfunction, in addition to airway mechanics," she said, "that I no longer think, as I did when I came to this, that it's just one thing. It's probably all of these things together."
In the meantime, questions about potential shared pathways for the development of obesity and asthma remain. "Obesity is a risk factor for developing asthma, but it's also entirely possible that asthma is a risk factor for developing obesity," she said. (Some data from pediatric populations, she noted, suggest that nonobese children with asthma are at increased risk of developing obesity.)
Also important, Dixon said, is "emerging literature in the last 5-10 years" that suggests that people with obesity are more susceptible to the effects of air pollution. Research involving inner-city schoolchildren with asthma, for instance, has shown that those with obesity had worse symptoms with air pollution exposure than did those who were not obese.
Pulmonary Arterial Hypertension
Some research has looked at adipose tissue–produced substances in PAH, but the most well-established association in obesity and PAH involves insulin resistance.
"I don't think we're certain as a community that obesity [in general] is the problem – it's not itself considered a risk factor for PAH," Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview. She noted that it's "hard to dissect obesity" apart.
Researchers are "more confident," she said, "that insulin resistance – one feature of obesity [in some people] – is associated with worse outcomes in PAH." Metabolic disease resembling insulin resistance is common in PAH and is believed to contribute to pulmonary vascular disease and right ventricular (RV) failure – the main cause of mortality in PAH – at least in part because of increased oxidative stress.
Hemnes led a mechanistic phase II clinical trial of metformin in PAH in which the drug was associated with improved RV fractional area change and reduced RV lipid deposition (J Am Heart Assoc. 2020;9:e018349), and she's now leading a National Institutes of Health–funded multicenter trial looking at the impact of metformin and an exercise intervention on 6-minute walk distance and World Health Organization functional class in PAH.
At the Rush Lung Center, in the meantime, Mokhlesi is utilizing animal models of OSA and OHS to explore the effect of hypoxia and nighttime hypercapnia on the development of PAH. "I think the jury is still out as to whether obesity itself is a major risk factor, but if so, by what mechanism?" he said. "Is it worsening [sleep-disordered breathing], which then worsens PAH?"
The focus in COPD has traditionally been on underweight, but the relationship between obesity and COPD has increasingly been recognized in the last 10-15 years, said Frits M. E. Franssen, MD, PhD, of CIRO, a research institute in Horn, the Netherlands, that treats COPD and other chronic lung diseases, and of the department of respiratory medicine at Maastricht University.
Researchers like Franssen are trying, for one, to understand obesity's impact on COPD pathophysiology and to tease apart the impact of both conditions on disease severity and patient-related outcomes such as exercise capacity and exercise-related symptoms.
When Franssen's group compared responses to weight-bearing exercise (6-min. walk test) and weight-supported exercise (cycling) in obese and normal weight COPD patients matched for age, gender, and degree of airflow limitation, the researchers found that walking capacity was significantly reduced while cycling capacity was preserved in the obese group (Respirology. 2016;21:483-8).
Exercise-related symptoms (dyspnea and leg fatigue) were largely comparable between the obese and normal-weight COPD patients in both exercise modalities. However, in other studies, dyspnea ratings during cycling – at any given level of ventilation – have been lower in obese patients, indicating that "additional fat mass may have a beneficial effect on lung functioning [in non–weight-bearing exercise]," he said in an interview.
Franssen's group also has assessed body composition in overweight and obese patients with COPD and found that a significant number have low muscle mass. These patients had worse lung function, exercise tolerance, and muscle strength compared to patients with comparable BMI and normal muscle mass (Respir Res. 2021 Mar 25. doi: 10.1186/s12931-021-01689-w).
"We'd always thought that obese patients have normal muscle mass ... but now we know it can be dramatically low," he said. In assessing obesity and formulating any weight loss plans, "we're now interested not only in weight but in the distribution of fat mass and fat-free mass ... and in maintaining muscle mass in patients who are [prescribed dietary interventions]."
Paradoxically, in patients with severe COPD, obesity is associated with prolonged survival, while in patients with mild to moderate COPD, obesity is associated with increased mortality risk, he noted.
The impact of adipose tissue and the chronic inflammation and metabolic disturbances that characterize obesity are currently largely unexplored, he said. Researchers have not yet studied what optimal weights may be for patients with COPD. "And we're interested in the questions, are body weight and body composition the result of the disease, or [are they] determining the type of COPD one will get?" Franssen said.
Patients with COPD who are obese have "more of the phenotype of chronic bronchitis," he noted, "while typical emphysema patients are normally underweight."
This article originally appeared on Chest Physician.
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Cite this: Obesity and Lung Disease: Much More Than BMI - Medscape - Jun 15, 2022.