Obesity-related Asthma: A Pathobiology-based Overview of Existing and Emerging Treatment Approaches

Abstract

Although obesity-related asthma is associated with worse asthma outcomes, optimal treatment approaches for this complex phenotype are still largely unavailable. This state-of-the-art review article synthesizes evidence for existing and emerging treatment approaches for obesity-related asthma and highlights pathways that offer potential targets for novel therapeutics. Existing treatments targeting insulin resistance and obesity, including metformin and GLP-1 (glucagon-like-peptide 1) receptor agonists, have been associated with improved asthma outcomes, although GLP-1R agonist data in asthma are limited to individuals with comorbid obesity. Monoclonal antibodies approved for treatment of moderate to severe asthma generally appear to be effective in individuals with obesity, although this is based on retrospective or secondary analysis of clinical trials; moreover, although most of these asthma biologics are approved for use in the pediatric population, the impact of obesity on their efficacy has not been well studied in youth. Potential therapeutic targets being investigated include IL-6, arginine metabolites, nitro-fatty acids, and mitochondrial antioxidants, with clinical trials for each currently underway. Potential therapeutic targets include adipose tissue eosinophils and the GLP-1–arginine–advanced glycation end products axis, although data in humans are still needed. Finally, transcriptomic and epigenetic studies of “obese asthma” demonstrate enrichment of IFN-related signaling pathways, Rho-GTPase pathways, and integrins, suggesting that these too could represent future treatment targets. We advocate for further study of these potential therapeutic mechanisms and continued investigation of the distinct inflammatory pathways characteristic of obesity-related asthma, to facilitate effective treatment development for this unique asthma phenotype.

Contents

• Treatments for Obesity

  • Metformin

  • GLP-1 Receptor Agonists

• Impact of Body Mass Index on Efficacy of Existing Monoclonal Antibody Treatments for Severe Asthma

  • Omalizumab

  • Dupilumab

  • Mepolizumab

  • Reslizumab

  • Benralizumab

  • Tezepelumab

  • Conclusions

• Potential Therapeutic Targets in Obesity-associated Asthma

  • IL-6 Inhibitors

  • Alterations in Arginine Metabolism

  • Nitro-Fatty Acids

  • Mitochondrial Antioxidants

• Potential Translational Mechanisms

  • Adipose Tissue Eosinophils

  • GLP-1–Arginine–Advanced Glycation End Products Axis

• Insights from Differential Expression and Methylation of Genes in Obese Asthma

  • IFN-related Signaling Pathways

  • Rho-GTPase Pathways

  • CDC42 Pathway

  • Integrins

• Conclusions and Future Directions

Despite the rising prevalence of obesity and asthma among both children and adults worldwide, the cooccurrence of obesity and asthma is more than coincidental (1, 2). The obese asthma phenotype is complex and likely bidirectional. It reflects both preexisting asthma that is worsened by obesity and asthma that is induced by underlying obesity (3–6). In all obesity-related asthma phenotypes, however, patients have worse asthma control and quality of life, have increased exacerbation rates, and represent a difficult-to-treat phenotype. Current treatment paradigms are not well defined and focus on a multimodal approach to target weight loss, common comorbidities including gastroesophageal reflux, and sleep apnea, and traditional asthma therapies (7–9). Although this approach yields some improvement in asthma management, there are a lack of current approved therapies that target non–type 2 (T2) inflammation that is common among obesity-driven asthma. In recent years, a better understanding of metabolic and immune mechanisms driving obesity-related asthma has identified potential therapeutic targets (6, 10–12). This review highlights mechanisms by which new treatments for obesity impact asthma, the impact of obesity on biologic therapy for asthma, and novel pathways targeting inflammation specific to obesity-driven asthma.

Treatments for Obesity

The nonpharmacologic management of obesity and, by extension, obesity-related asthma, includes weight loss through diet modification, increased physical activity, and bariatric surgery. These topics have been extensively reviewed elsewhere (7, 9, 13). Weight loss through lifestyle interventions has been shown to improve asthma control and quality of life among those who lost at least 5% of their preintervention body weight (14–18). Bariatric surgery in obesity-related asthma has demonstrated improvements in asthma control, medication use, and exacerbations after surgery (19–24), and a meta-analysis of bariatric surgery in asthma found significant improvements in FVC and FEV₁, although no change in FEV₁/FVC ratio, likely reflecting improvement in extrathoracic restriction with weight loss (25). Metabolic syndrome, however, appears to play a role in response to nonpharmacologic weight loss interventions. Among those with asthma who underwent bariatric surgery, only those without metabolic syndrome had long-term improvement in asthma control (24). Inflammation from metabolic syndrome may be driving asthma symptoms in some patients, and targeting these pathways may be novel therapeutic options for patients with obesity-related asthma.

Metformin

Metformin is a readily available first-line medication for insulin resistance in diabetes. Retrospective cohort studies have generally found decreased asthma incidence and, among those with preexisting asthma, decreased emergency department visits and hospitalizations for asthma exacerbations in adults (26–29) and decreased outpatient asthma exacerbations in adolescents (30). In a notable exception, Yen and colleagues found higher asthma incidence and severe exacerbations with metformin use, most of which occurred after at least 2 years of use (31). The association between metformin and asthma outcomes is difficult to fully understand from retrospective studies, particularly as insulin use was included in the non-metformin comparator group in several studies. Insulin itself has been shown to increase asthma risk (29, 32) and increase airway hyperresponsiveness (33). Metformin has been shown to have antiinflammatory properties in murine models of obese asthma, including a reduction in TNF-α and IL-4 and increases in regulatory T cells (34, 35).

GLP-1 Receptor Agonists

GLP-1R (glucagon-like-peptide 1 receptor) agonist medications, most notably semaglutide, liraglutide, and tirzepatide (GIPR [GLP-1R/glucose-dependent insulinotropic peptide receptor] agonist), have U.S. Food and Drug Administration indications for the treatment of obesity. These medications work by slowing gastric emptying time, blocking glucagon secretion, increasing insulin secretion, and increasing satiety (36). They have been shown to lead to significant weight reduction in adults and adolescents with obesity (37–39). Metformin has been shown to increase GLP-1 concentrations in plasma (40), and bariatric surgery is associated with increased endogenous production of GLP-1, which is associated with increased postsurgical weight loss (41). In addition to their weight loss effects, there are potential mechanisms to suggest that the GLP-1R agonists may modify airway inflammation in obese asthma and represent a novel treatment to target for the treatment of obesity and asthma.

Epidemiologic data

The limited epidemiologic data on GLP-1R agonists in asthma are largely retrospective; however, they point to potential beneficial effects of these medications on asthma outcomes in obesity. In a retrospective cohort study using electronic health record data, Foer and colleagues compared exacerbation rates of patients with asthma and type 2 diabetes (DM2) initiating diabetes-targeted therapies. Patients receiving GLP-1R agonists experience lower rates of asthma exacerbation than those on SGLT2 (sodium-glucose cotransporter-2) inhibitors, DDP-4 (dipeptidyl peptidase-4) inhibitors, sulfonylureas, and basal insulin (42). Similar findings have been shown in patients with chronic obstructive pulmonary disease (43, 44). A national claims database study found that there were fewer exacerbations of chronic lower respiratory disease (chronic obstructive pulmonary disease and asthma) among those receiving GLP-1R agonist therapy compared with DDP-4 inhibitors and sulfonylureas; however, in subgroup analyses, GLP-1R agonists were not associated with decreased hospitalizations for asthma, although other outcomes were not stratified by chronic lung disease diagnosis (45).

In the only prospective study to date, Khan and colleagues followed nine patients with asthma and DM2 who were treated with liraglutide for 52 weeks. Mean weight loss was only 5.6% of baseline weight; however, there were significant improvements in asthma control among those who lost weight, although notably mild and moderate exacerbations decreased regardless of weight loss (46). Although GLP-1R agonist dosing was not explicitly stated, given that patients had comorbid DM2, it is assumed that they received the DM2 dose rather than the higher dose that is used for obesity.

Proposed mechanisms in asthma

GLP-1R is found on diverse cell and tissue types throughout the body, including airway smooth muscle, type II pneumocytes, epithelial cells, eosinophils, neutrophils, and platelets (47–49). In murine models of allergic asthma, GLP-1R agonists have been shown to impact markers of T2 and non-T2 inflammation (Figure 1). In allergic obese mouse models, administration of liraglutide has attenuated airway hyperresponsiveness (AHR) after exposure to ovalbumin and decreased airway resistance to methacholine after Alternaria exposure, believed to be driven by changes in T2 inflammation (50, 51). Pretreatment with liraglutide has led to decreased airway eosinophils and T2 cytokines IL-4, IL-5, IL-13 and decreased recruitment of group 2 innate lymphoid cells in the BAL, and decreased IL-5, IL-13, IL-1β, CXCL1, CXCL5, CCL11, and CCL24 in lung homogenate in murine obese allergic asthma models (50, 51). Similar findings were seen with tirzepatide, which found further reduction in lung T2 cell counts and IL-33 compared with semaglutide in obese mice (52). In an aspirin-exacerbated respiratory disease murine model, administration of liraglutide prevented aspirin-induced increases in airway resistance, platelet recruitment to the lung, and attenuated BAL levels of CXCL7, a platelet-derived chemokine (49). Platelets from patients with aspirin-exacerbated respiratory disease and control subjects were exposed ex vivo to thromboxane receptor agonists to induce platelet activation with or without liraglutide pretreatment. In both groups, liraglutide pretreatment was associated with decreased CXCL7 in the plasma and P-selectin, a platelet activation marker, expression (49). Finally, serum periostin, a biomarker of T2 asthma, has been shown to be decreased in biobank samples of patients with comorbid asthma and DM2 prescribed GLP-1R agonists compared with those not on this therapy, and periostin levels decrease after treatment with GLP-1R agonists compared with sitagliptin or a dietary intervention in a randomized controlled trial in participants with DM2 without asthma (53).

Figure 1.

Potential impact of GLP-1R agonists on T2 and non-T2 inflammation from preclinical models of asthma. Blue font indicates data from murine models of asthma and obesity, brown font indicates data from humans with asthma and diabetes, green font indicates murine model of aspirin-exacerbated respiratory disease, not obesity. CXCL7 = C-X-C motif ligand 7; GLP-1RA = glucagon-like-peptide-1 receptor agonist; ILC2 = group 2 innate lymphoid cells; TSLP = Thymic stromal lymphopoietin. Created using BioRender.com.

Obesity-related asthma is often associated with non-T2 inflammation, and there is emerging evidence that GLP-1R agonists influence inflammatory pathways that may be relevant in this asthma phenotype. In addition to decreased T2 inflammation, IL-1β and the NLRP3 (nucleotide oligomerization domain-like receptor protein 3) inflammasome decreased after liraglutide treatment (50). The NLRP3 inflammasome has been shown to be increased in obese patients with asthma, and this is the first preclinical study to show decrease in this inflammatory pathway with GLP-1R agonists (54). In a study by Toki and colleagues, obese mice had more BAL neutrophils than lean mice, and liraglutide attenuated neutrophilic inflammation seen in the BAL of obese mice (51). In a murine model, GLP-1R was found to be expressed by T cells; it was associated with allograft survival in a transplant model and had anti-tumor immunity in a colorectal cancer model, providing evidence that GLP-1R may have a T cell–negative costimulatory model with antiinflammatory properties (55).

Future directions

Strong preclinical data suggest that GLP-1R agonists may influence the pathophysiology of obesity-related asthma beyond mechanical benefits of weight loss. These models show consistent improvements in T2 inflammation, and there are novel pathways suggesting modification of important drivers of non-T2 inflammation specific to obesity-related asthma. There are several important limitations to the existing knowledge base that are worth noting. First, the inflammatory effects of GLP-1R agonists are seen predominantly in murine models; however, there are differences in GLP-1R tissue distribution across species (56). Unlike in humans, there is reduced potency of GIPR effects in mice (57), making inferences on the effects of the dual GIPR/GLP-1RA in asthma difficult to determine in this model. The clinical data in humans are largely retrospective in patients with comorbid diabetes, and the only prospective study did not have a control group. Finally, there is a lack of data on the effects of GLP-1R agonists on asthma in children and adolescents.

To address these limitations and explore the potential of this class of medications in obesity-associated asthma, prospective, randomized trials are needed to understand the potential benefit of GLP-1R agonists in patients with asthma. A prospective, randomized, double-blind, placebo-controlled phase II study of semaglutide 2.4 mg weekly, the dose approved for weight loss, in adults with obesity-related, symptomatic asthma is actively enrolling, with a target completion in 2026 (NCT05254314). Other drugs, including dual agents like tirzepatide, are also potential therapeutic targets in need of clinical trial data.

Impact of Body Mass Index on Efficacy of Existing Monoclonal Antibody Treatments for Severe Asthma

Although the obesity-related asthma phenotype is heterogeneous, obesity can worsen underlying T2-high asthma. Although many individuals with obese asthma meet eligibility criteria for monoclonal antibody therapy based on presence of T2 inflammation, there is limited and conflicting evidence regarding if or how body mass index (BMI) impacts the efficacy of monoclonal antibodies for asthma (Table 1).

Table 1.

Summary of Findings from Studies Examining Response to Asthma Biologic Therapies by BMI or Obesity

Monoclonal Antibody	Impact of BMI on Treatment Response
	Neutral	Positive	Negative
Children
Omalizumab	Asthma control (60) Reduction in ICS dose (60)	Exacerbation rate reduction (60)	—
Adults
Omalizumab	Exacerbations (65, 68) FEV1 (61, 64, 68) Asthma control (61, 64, 65, 68) Reduction in ICS dose (61, 65)	Exacerbation rate reduction (61) FEV1 (63, 67) Asthma control (62, 63)	Exacerbations (62–64) FEV1 (65) Asthma control (66, 67)
Dupilumab	Exacerbation rate reduction (69, 70) FEV1 (69, 70)	—	Asthma control (70)* Clinical remission (72)
Mepolizumab	Exacerbation rate reductions (75, 78–80) Asthma control (75, 78–80) FEV1 (78–80)	—	Asthma control (82) FEV1 (75) Being a “super-responder”† (83)
Reslizumab	Exacerbations (84)	—	—
Benralizumab	Being a “responder”‡ (88)	—	Exacerbation rate reduction (87) FEV1 (87)
Tezepelumab	Exacerbations (93, 94)	—	—

Definition of abbreviations: BMI = body mass index; ICS = inhaled corticosteroid; OCS = oral corticosteroid.

^*Placebo favored over dupilumab for individuals treated with high-dose ICSs at baseline and BMI ⩾ 30.

^† Super-responder defined as being in the top quartile of percentage reduction in maintenance OCS dose, while having a synchronous reduction in exacerbations; or if not on maintenance OCS, had the top quartile of percentage reduction in exacerbations.

^‡ Responders defined as having ⩾50% reduction in exacerbations and/or OCS maintenance dose.

Omalizumab

Omalizumab is an anti-IgE monoclonal antibody approved since 2003 for treatment of severe allergic asthma in individuals ⩾6 years old that has been shown to reduce exacerbations, reduce asthma symptoms, and improve asthma quality of life (58). Omalizumab dosing is based on weight and total IgE level; there are no dosing options for individuals >150 kg. Post hoc analyses of the pediatric Inner-City Anti-IgE Therapy for Asthma trial (59) examined treatment response based on BMI < 25 kg/m² or ⩾25 kg/m² and found no significant difference in reduction in asthma symptom days or reduction in inhaled corticosteroid (ICS) use with omalizumab compared with placebo by BMI category after 60 weeks of treatment. Interestingly, they found that the higher BMI subgroup had higher odds of reduced asthma exacerbations with omalizumab than the subgroup with lower BMI (60). These findings are difficult to interpret, however, as z-score, not BMI, is standard for defining overweight and obesity in children.

In post hoc analyses of two clinical trials of omalizumab in adults, investigators compared treatment response among three subgroups: normal BMI (<25 kg/m²), overweight (BMI 25 to <30 kg/m²), and obese (BMI ⩾ 30 kg/m²). After 16 weeks of treatment, they found no differences in FEV₁ or ICS dose reduction by BMI category. Increasing BMI was associated with greater placebo-adjusted exacerbation rate reductions but trended toward smaller improvements in total Asthma Symptom Score and Asthma Quality-of-Life Questionnaire (61).

Multiple observational studies in adults have examined the association between BMI and omalizumab response with conflicting findings. Some have found that increased BMI is associated with lower reduction in exacerbations (62–64), lower improvements in FEV₁ (65), and worse improvements in asthma control (66, 67). In contrast, other observational studies reported that increased BMI is associated with greater improvements in FEV₁ (63, 67) and asthma control (62, 63). Yet, other studies reported no differences in exacerbation rate reductions (65, 68), improvement in FEV₁ (61, 64, 68), improvement in asthma symptom control (61, 64, 65, 68), or reductions in ICS dose (61, 65) based on BMI or obesity.

Dupilumab

Dupilumab is a monoclonal antibody that inhibits the signaling of IL-4 and IL-13 by binding to IL-4Rα, approved for the treatment of severe eosinophilic or T2-high asthma in individuals ⩾6 years of age. It has been shown to reduce exacerbations, reduce symptoms, and improve lung function (58) and has been approved for use in the United States since 2018. Two post hoc analyses (69, 70) of the Asthma Liberty QUEST trial (71) found no difference in dupilumab treatment response by BMI category. The first, which included adolescents and adults, found similar decreases in annualized asthma exacerbation rates after 52 weeks for BMI < 25, BMI 25 to <30, and BMI ⩾ 30 (overall P value for the interaction = 0.59), as well as similar improvements in FEV₁ after 12 weeks of treatment with dupilumab (overall P value for the interaction = 0.27) (69). The second, which examined BMI < 30 versus ⩾30, found similar decreases in annualized exacerbation rates and improvement in FEV₁ with dupilumab across BMI categories, with similar results for both the 200-mg and 300-mg every-2-weeks dosing regimens (70). Among individuals with high-dose ICS and BMI ⩾ 30, there was no statistically significant difference in improvement of Asthma Control Questionnaire-5 (ACQ-5) with placebo versus dupilumab. All other ACQ-5 analyses (high- or medium-dose ICS; BMI < 30 or ⩾30) favored dupilumab over placebo, although not all results were statistically significant (70).

A small prospective study followed 20 adults with severe uncontrolled eosinophilic asthma prescribed dupilumab for 24 months and examined the relationship between obesity and clinical remission. They found that obesity was associated with decreased odds of clinical remission (odds ratio, 0.03; 95% confidence interval, 0.002–0.41; P = 0.004) among obese patients (72). These were unadjusted results with a small sample size; therefore, they should be interpreted with caution.

Mepolizumab

Mepolizumab is a monoclonal antibody that targets IL-5 and inhibits eosinophilic inflammation used to treat patients ⩾6 years old with severe eosinophilic asthma, approved in the United States in 2015. It has been shown to decrease exacerbations, reduce symptoms, and have a small or moderate effect on FEV₁ (58). Albers and colleagues conducted a large post hoc individual patient-level meta-analysis of data of Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) (73) and Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Participants With Severe Eosinophilic Asthma on Markers of Asthma Control (MUSCA) (74) to determine if BMI influenced the effect of mepolizumab on exacerbations, lung function, and asthma control. They found significant reductions in exacerbations across all BMI categories of mepolizumab versus placebo: 62% decrease for BMI ⩽ 25 kg/m², 55% decrease for BMI > 25 to 30 kg/m², and a 49% decrease for BMI > 30 kg/m², with overlapping confidence intervals. Mepolizumab was also associated with similar improvements in baseline ACQ-5 score across BMI categories. Mepolizumab treatment was associated with significant increases in FEV₁ for the groups with a normal BMI or overweight but not for the group with obesity (75).

A post hoc meta-analysis of data from four randomized studies of mepolizumab (MENSA [73], MUSCA [74], DREAM [Dose Ranging Efficacy and Safety with Mepolizumab Study] [76], and SIRIUS [Steroid Reduction with Mepolizumab Study] [77]) compared the effects of mepolizumab by presence or absence of obesity. They found no difference in exacerbations, ACQ-5 scores, or St. George’s Respiratory Questionnaire scores by obesity status. Although there was an increase in FEV₁ after mepolizumab for the nonobese group, there was not a statistically significant change in FEV₁ in the obese group (78). Two observational studies similarly found no difference in response to mepolizumab by BMI category (79, 80), and an observational study of obese individuals with asthma reported significant decreases in exacerbations and asthma-related outpatient and emergency department visits with mepolizumab (81).

Conversely, an observational study of adolescents and adults with severe eosinophilic asthma treated with mepolizumab found that BMI ⩾ 30 attenuated ACQ-5 improvement. They also found that participants in the top quartile of ACQ-5 responses to mepolizumab had a significantly lower BMI than those in the lower three quartiles and that patients who achieved asthma control after 6 months of treatment with mepolizumab had a lower BMI than those who did not (82). Similarly, another small observational study of adults with severe asthma treated with mepolizumab found that “super-responders” had a significantly lower BMI and were significantly less likely to have a history of obesity (83).

Reslizumab

Reslizumab, a monoclonal antibody dosed by weight, binds to circulating IL-5 and has been shown to reduce exacerbations, reduce symptoms, improve quality of life, and have a small or moderate effect on FEV₁ in individuals with severe eosinophilic asthma (58). It has been approved in the United States since 2016 for the treatment of severe eosinophilic asthma in individuals ⩾18 years old. A single post hoc analysis of pooled data from duplicate phase 3 trials (part of the BREATH program) examined the impact of BMI (<25 or ⩾25) on asthma exacerbations after 52 weeks of treatment in adolescents and adults with uncontrolled eosinophilic asthma receiving oral corticosteroids at baseline. Both BMI groups had reductions in asthma exacerbations with reslizumab, with no significant difference between the BMI groups (84).

Benralizumab

Benralizumab is a monoclonal antibody that depletes eosinophils by binding to IL-5Rα. It is approved for the treatment of severe eosinophilic asthma in individuals ⩾12 years old and has been shown to reduce exacerbations, reduce symptoms, improve quality of life, and have a small or moderate effect on FEV₁ (58). It was approved for use in the United States in 2017.

A post hoc pooled analysis of efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO) (85) and Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist (CALIMA) (86) examined the impact of benralizumab versus placebo by BMI >35 or ⩽35 on annualized exacerbation rate and FEV₁. They found improvements in both exacerbation rate and FEV₁ with benralizumab compared with placebo with both dosing intervals (every 4 wk or every 8 wk) among those with BMI ⩽ 35, but no significant difference in exacerbations or FEV₁ in those with BMI > 35 (87). An observational registry study (Dutch Register of Adult Patients with Severe Asthma for Optimal DIsease management [RAPSODI]) of adults who started benralizumab for severe eosinophilic asthma examined predictors of benralizumab response. They found no statistically significant difference in the BMI of responders, defined as having a ⩾50% reduction in annual exacerbation frequency or a ⩾50% reduction in oral corticosteroid maintenance dose after 12 months of treatment, versus nonresponders (88).

Tezepelumab

Tezepelumab is an anti-thymic stromal lymphopoietin monoclonal antibody used for treatment of severe asthma in individuals ⩾12 years old. It has been shown to reduce exacerbations, reduce symptoms, improve lung function, and improve quality of life (58). Approved in 2021, it is the most recently approved asthma biologic in the United States and the only monoclonal antibody that can be used to treat asthma in individuals without a T2-high profile, which is particularly salient given reports associating obese asthma with more neutrophilic than eosinophilic inflammation (89, 90). Post hoc pooled analysis of Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma (PATHWAY) (91) and study to evaluate tezepelumab in adults & adolescents with severe uncontrolled asthma (NAVIGATOR) (92) examined the effect of tezepelumab on exacerbations and exacerbation-related hospitalizations by BMI group. They found similar, statistically significant reductions in exacerbations and exacerbation-related hospitalizations after 52 weeks of treatment across BMI groups (<25, 25 to <30, and ⩾30 kg/m²) (93). Likewise, a separate post hoc analysis of NAVIGATOR found similar reductions in asthma exacerbations across BMI groups (<25, 25 to <30, and ⩾30 kg/m²) (94).

Conclusions

Overall, monoclonal antibody therapies for asthma appear to be effective in obese individuals; however, there are notable limitations and heterogeneity in findings in this literature. The quality of existing evidence is significantly limited by study design: studies are either retrospective or secondary analyses of trials, which increases the likelihood of bias. In addition, studies examined obese individuals as a single group (i.e., BMI ⩾ 30); there are limited data regarding the efficacy of biologics at the extremes of the BMI spectrum. The participants in most of these clinical trials were not representative of the general population with uncontrolled asthma, in that they were older, had a lower BMI, and were more likely to identify as White (95). Ideally, future studies will include racially and ethnically diverse populations at multiple centers to increase the generalizability of the findings and will include more children, who were largely excluded from existing studies. Further studies are needed to understand if and how adiposity influences treatment response to existing asthma biologics, particularly biologics such as dupilumab with multiple dosing regimens. Because BMI is only a limited anthropometric proxy for adiposity (96), subsequent studies should examine other indices, such as waist-to-hip ratio or body fat composition.

In addition, individuals with obese asthma may benefit from a more targeted treatment approach with asthma biologics. Mice models of obese asthma demonstrated that treatment with a PPAR-γ (peroxisome proliferator-activated receptor-γ) agonist limited development of T17 pathology and unlocked therapeutic responsiveness to T2 biologic therapies (97). Although PPAR-γ agonists in humans have not been shown to improve obese asthma outcomes and were associated with significant adverse events (98, 99), a different precision medicine approach targeting the immune dysregulation caused by obesity may help optimize response to T2 biologic therapies in obese asthma.

Potential Therapeutic Targets in Obesity-associated Asthma

IL-6 Inhibitors

In both children and adults, obese asthma is less likely to be associated with eosinophils and T2 inflammation and more likely to be associated with neutrophils and T1/T17 inflammation (89, 90). Obesity promotes secretion of proinflammatory cytokines from adipocytes and inflammatory macrophages, resulting in chronic low-grade systemic inflammation (100). One such inflammatory cytokine is IL-6, which is elevated in a subgroup of children and adults with asthma (101, 102). Multiple studies of individuals with asthma have found that elevations in plasma IL-6 are associated with higher BMI (101–104). Active IL-6 and soluble IL-6R signaling have been shown to be increased in patients with asthma with low eosinophil counts (105) or low T2 inflammation in the lungs (106), suggesting that IL-6–related inflammation is inversely related to T2 inflammation. Higher IL-6 values have also been associated with exacerbation-prone asthma (107). For the subgroup of individuals with asthma and elevated IL-6, particularly for those without an optimal response to T2 asthma biologics, IL-6 blockade is an appealing potential therapy (12) (Figure 2). A case series of two children with poorly controlled, steroid-resistant, severe persistent asthma with mild peripheral eosinophilia, normal IgE, and negative allergy testing reported clinical and immunological responses to tocilizumab, an anti–IL-6 receptor monoclonal antibody (108). A phase II clinical trial of clazakizumab, an anti–IL-6 monoclonal antibody, for treatment of severe asthma is ongoing (NCT04129931) (109). After conclusion of the trial, it will be valuable to conduct post hoc analyses of BMI and treatment response.

Figure 2.

Proposed mechanisms and impact of investigational therapeutics on nitro-oxidative stress in obesity-related asthma. Green boxes indicate data from human case series or pilot trials, dark blue boxes indicate data from murine models. ADMA = asymmetric dimethylarginine; AGE = advanced glycation end products; GLP-1 RA = glucagon-like-peptide-1 receptor agonist; MitoQ = mitoquinol; mtROS = mitochondrial reactive oxygen species; NF-κB = nuclear factor kappa B; NLRP3 = nucleotide oligomerization domain-like receptor protein 3; NO = nitric oxide; NO₂-OA = nitro-oleic acid; NOS = nitric oxide synthase; PKA = protein kinase A; PRMT-1 = protein arginine methyltransferase-1; RAGE = receptor of advanced glycation end products. Created using BioRender.com.

Alterations in Arginine Metabolism

Overview of l-arginine and nitric oxide metabolism

Arginine is a necessary substrate for the generation of airway nitric oxide (NO) and citrulline by NO synthase (NOS). The balance of arginine metabolism through NOS and arginase influences airway NO and plays a role in asthma pathogenesis (110, 111). The production and relative abundance of asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, also plays a role in the production of NO and oxo-nitrative stress from reactive oxygen species (ROS) and reactive nitrogen species via NOS uncoupling (112). Although elevated fractional exhaled nitric oxide (Fe_NO) is classically considered a marker of poorly controlled asthma in those with T2-driven inflammation, it is well documented that those with obesity-related late-onset asthma are more likely to have lower Fe_NO levels (113). Reduced NO airway bioavailability is believed to play a mechanistic role in driving asthma symptoms in this population, and interventions targeting perturbations in arginine metabolism offer promise for a novel treatment for obesity-related asthma.

Epidemiologic data

Arginine metabolism is uniquely altered in obesity-related asthma (Figure 3). In prospective and cross-sectional studies of patients with asthma, increasing BMI is associated with increased ADMA, decreased arginine/ADMA, and decreased citrulline levels (114, 115). Decreased arginine/ADMA was associated with increased asthma symptoms and decreased lung volumes and asthma quality of life in late-onset asthma, which is commonly associated with obesity, but not in early-onset asthma (115). Compared with patients with lean asthma and lean and obese control subjects, the bronchial airway epithelial cells from patients with obese asthma have increased arginase activity and higher levels of 3-nitrotyrosine, a reactive nitrogen species, indicating more NOS uncoupling in obese asthma compared with lean asthma and both controls (116). Although not in an asthma-specific cohort, obesity in adolescents and diabetes in adults were associated with increased ADMA, which decreased after a weight-loss intervention (117). Together, this literature suggests that those with obesity-related asthma have higher ADMA and increased nitro-oxidative stress compared with other asthma phenotypes.

Figure 3.

Epidemiologic associations of arginine metabolism, asthma, and obesity. Increasing concentrations of arginine metabolites (blue) and increasing concentrations of arginine metabolite ratios (yellow), which approximates enzyme activity and their associations with asthma outcomes and BMI. ADMA = asymmetric dimethylarginine; Arg = arginine; BMI = body mass index; Cit = citrulline; NOS = nitric oxide synthase; OAT = ornithine aminotransferase; ODC = ornithine decarboxylase; Orn = ornithine.

Proposed mechanisms

There are several perturbations in arginine metabolism that are believed to influence asthma pathogenesis, although most proposed mechanisms focus on decreased generation of airway NO and increased generation of ROS and reactive nitrogen species leading to oxidative and nitrosative stress (Figure 2). This is believed to occur via decreased arginine substrate for NOS, either via low arginine bioavailability or increased metabolism via arginase. ADMA inhibition of NOS leads to uncoupling producing superoxide and peroxynitrite (110, 111). Although these mechanisms have been shown to occur in multiple asthma phenotypes, including T2-driven inflammation, there appear to be alterations in arginine metabolism in obesity-related asthma that may offer novel therapeutic targets. Mice with metabolic syndrome have been shown to have increased AHR to methacholine, increased ADMA, decreased arginine/ADMA, and decreased arginine bioavailability compared with mice without metabolic syndrome, indicating a potential mechanism between metabolic syndrome, obesity, and asthma through changes in arginine metabolism (118). Obese and nonobese mice with metabolic syndrome also had increased NOS and arginase in lung tissue, although decreased Fe_NO compared with controls, suggestive of NOS uncoupling from increased ADMA (118).

Therapeutic interventions

In animal studies, inhalational arginine has been shown to reverse AHR to allergens (119, 120), and oral arginine decreased AHR and decreased airway eosinophils and T2 cytokines, including IL-5, IL-4, and IL-13 (121). Arginine supplemental trials in humans, however, have not demonstrated reduction in exacerbations or improvement in lung function (122, 123). Arginine undergoes significant first-pass metabolism by the liver after ingestion (124), which may explain the lack of effectiveness to date in clinical studies.

Another approach to increasing arginine bioavailability is through citrulline supplementation. The addition of citrulline to human airway epithelial cells has been shown to increase arginosuccinate, the enzyme that converts citrulline to arginine, and prevents NOS uncoupling by ADMA (125, 126). This leads to a restoration of airway NO and prevents oxo-nitrative stress. This is supported by epidemiologic data that have shown increased citrulline to be associated with improved asthma control (114). In a proof-of-concept study, 41 patients with obesity, asthma, and low Fe_NO were given 15 g/d of oral citrulline supplementation for 2 weeks. Participants had an average increase in Fe_NO of 4.2 ppb, improved asthma control, and significant improvements in FVC of 86 ml and FEV₁ of 52 ml after citrulline supplementation (127). Although more work is needed, this is a promising novel therapy for obesity-related asthma.

Future directions

Robust data implicate dysregulation of arginine metabolism in the pathophysiology of asthma, but additional work is needed to understand the potential therapeutic benefits from targeting this pathway. Early clinical data on citrulline supplementation are encouraging; however, larger, randomized trials are needed. The impact of citrulline supplementation is being studied in a phase 2 randomized crossover trial in obesity-related asthma with low Fe_NO (NCT03885245) and in veterans with deployment-related asthma (NCT05259904), both of which are currently enrolling patients. There are currently no trials registered investigating inhaled arginase inhibitors in humans, and more work needs to be done in this area given the promising yet complicated findings in animal models.

Nitro-Fatty Acids

Increased nitro-oxidative stress is a potential mechanism of inflammation in obesity-related asthma. Electrophilic fatty acids are formed via enzymatic and oxidative reactions and have antiinflammatory and antifibrotic properties that modulate redox signaling pathways (128–130). Supplementation with nitro-oleic acid (NO₂-OA), a nitro-fatty acid, is being investigated as a possible treatment for metabolic diseases associated with systemic inflammation, including pulmonary hypertension, hepatic steatosis, and dilated cardiomyopathy in obese mouse models (131–134), and is a potential target for obesity-related asthma.

Metabolomics studies have identified differences in bile acid profiles between those with and without asthma (135–137), and obesity is associated with increased bile acids and free fatty acids (138). Obese patients with asthma have been shown to have higher levels of bile acids than those with lean asthma and obesity without asthma and increasing bile acids correlated with decreased FEV₁ (135). In an obese asthma murine model, administration of NO₂-OA decreased airway hyperreactivity to methacholine and measures of airway resistance and elastance but did not change mucus production (135, 139). Two studies found decreased total cell counts in BAL fluid after NO₂-OA treatment, but inflammatory cytokine levels were not impacted (135, 139). Using a multiomics approach, treatment with NO₂-OA in mice with obesity and allergic asthma decreased expression of Pycr1 and proline synthesis in the lung, leading to improvements in lung elastance (139). This study also found changes in the gut microbiome after NO₂-OA treatment that were associated with decreases in microbes associated with decreased lung function (139). In a study on inhaled NO₂-OA in ovalbumin-sensitized mice, NO₂-OA had similar antiinflammatory properties to inhaled fluticasone, although NO₂-OA treatment led to increased neutrophil apoptosis, indicating a possible benefit among patients with asthma with neutrophil-predominant inflammation (140).

Administration of systemic NO₂-OA is a promising therapeutic target for obesity-related asthma; however, there are limited prospective data in humans. There is an ongoing phase 2 placebo-controlled crossover trial evaluating the effect of CXA-10, a synthetic NO₂-OA, on AHR and inflammation in obese patients with asthma (NCT03762395).

Mitochondrial Antioxidants

Obese asthma is associated with increased oxidative stress, formation of ROS, and increased NF-κB (nuclear factor-κB) expression, which is driven in part by increased mitochondrial respiration and altered bioenergenesis (11, 116, 141, 142) and is associated with increased exacerbations (143). MitoQ, also called mitoquinol or mitoquinone, is a derivative of ubiquinone and a mitochondria-localized antioxidant. MitoQ has been shown to decrease inflammation in small cardiovascular disease studies (144), but there are no clinical data in humans with asthma. In a murine model of steroid-insensitive asthma, treatment with MitoQ decreased AHR, airway inflammation, and production of ROS (145). Similarly, obese and lean house dust mite–sensitized mice treated with MitoQ had decreased AHR, inflammation, and remodeling in both weight groups. The obese group had increased tissue eosinophilia compared with the lean group; however, this was decreased by MitoQ treatment (146). In human bronchial epithelial cells, exposure to particulate matter ⩽2.5 μm in aerodynamic diameter led to increased mitochondrial stress, which was reversed with MitoQ exposure (147).

The NLRP3 inflammasome may mediate inflammation in obesity-related asthma through mitochondrial ROS (mtROS) (Figure 2). Human bronchial epithelial cells incubated with leptin, which is increased in obesity, demonstrated disruption in mitochondrial membranes leading to increasing in mtROS (148). Treatment with MitoQ led to recovery of mitochondrial membranes and restoration of mtROS levels to baseline. Similarly, expression of NLPR3-related genes was increased in the leptin group compared with control, which then decreased after MitoQ treatment (148).

A phase 1 randomized clinical trial investigating the impact of MitoQ in obesity-related asthma is ongoing (NCT04026711) and will provide insight into the potential benefit of mitochondrial antioxidants in obesity-related asthma.

Potential Translational Mechanisms

Adipose Tissue Eosinophils

Adipose tissue is recognized as an endocrine organ that plays a role in energy expenditure, glucose and insulin tolerance, and maintaining body temperature. In obesity, adipose tissue function is impaired and has systemic metabolic and inflammatory effects. There is increasing interest in understanding the role of adipose tissue eosinophils (ATEs) in obesity and determining if this offers a novel therapeutic target for obesity-related asthma (149). Recent work has shown distinct transcriptional profiles of ATEs compared with circulating and other tissue-resident eosinophils and found differential expression of a number of regulatory transcription factors, indicating differences in this eosinophil population (150). In murine models, ATEs are largely considered beneficial and play a role in glucose and metabolic homeostasis and thermogenic beige fat activation through T2 signaling leading to macrophage switching to M2 cells and activation of group 2 innate lymphoid cells (151–158). In mice fed a high-fat diet, the absence of eosinophils led to glucose intolerance and insulin resistance, suggesting that eosinophils play an important role in metabolic homeostasis (152, 156). Even in animal models, this relationship is not straightforward: repletion of eosinophils was not sufficient to reestablish metabolic homeostasis in murine models of obesity (159).

Data from humans are less convincing that ATEs play a protective role in obesity and metabolic syndrome. There is an epidemiologic association between increasing circulating eosinophils and BMI and metabolic syndrome in nonasthma populations (160, 161). Several studies have found that use of the anti-eosinophil biologics mepolizumab and benralizumab were associated with weight loss, although this was predominantly in the subgroup on chronic oral corticosteroids, making the inference between decrease in eosinophils and weight difficult to interpret (162–164). A study of subcutaneous ATEs from human biopsies found that circulating eosinophils and ATEs were higher in those with metabolic syndrome compared with those without. ATEs correlated with glucose, free fatty acids, IL-6, insulin resistance, and leptin (165).

Additional work is needed, particularly in humans, to better understand the role ATEs play in obesity and if an association exists between ATEs in asthma pathophysiology and burden in obesity. This is likely a complex relationship, as there exist phenotypes of T2-high asthma made worse by obesity and obesity-driven inflammation leading to T2-low asthma. This is further supported by data that have shown that adipose tissue T2 cells are associated with decreased inflammation, decreased weight gain, and decreased insulin resistance in human and murine models, suggesting that T2 cells promote adipose tissue health in the face of adipose tissue dysregulation associated with obesity (166–168). There are no data to date quantifying and investigating the consequences of potential differences in ATEs in these groups.

GLP-1–Arginine–Advanced Glycation End Products Axis

Another promising pathway influencing non-T2 inflammation in obesity-related asthma is the formation of advanced glycation end products (AGEs). AGEs are nonenzymatically glycosylated proteins and lipids that can modulate inflammatory responses (169). Hyperglycemia, dyslipidemia, and oxidative stress accelerate the formation of AGEs. AGEs interact with their receptor (RAGE), which drives inflammation and oxidative stress via NF-κB. Increased RAGE ligands have been found in sputum of patients with asthma and mouse models of asthma, and, in humans, its concentrations are inversely related to FEV₁ and FEV/FVC ratios (170, 171) (Figure 2). In mouse models of asthma, RAGE inhibition was associated with decreased T2 cytokines IL-4, IL-5, and IL-13, BAL neutrophils, eosinophils, and peribronchial inflammation (171, 172).

GLP-1R agonists and arginine metabolites are implicated in AGE–RAGE interactions and are hypothesized to act in concert to promote inflammation in obesity-related asthma through the GLP-1–arginine–AGE–RAGE axis. GLP-1R agonists activate PKA, which inhibits the transcription of NF-κB, which is the proposed mechanism by which GLP-1R agonists can attenuate the proinflammatory effects of AGE–RAGE interactions (173). The effects of GLP-1R agonists have not directly been studied on AGEs and RAGE in asthma; however, they have been shown to decrease RAGE expression in a rat model of nonalcoholic hepatic steatosis (174). l-arginine supplementation has been shown to increase GLP-1 (175) and has been associated with increased urea (176). GLP-1R agonists have been shown to inhibit ADMA via PKA activation and to downregulate expression of PRMT-1, the enzyme that drives ADMA production in animal models (173, 177). Hypotheses that the GLP-1–arginine–AGE–RAGE axis plays a role in the pathogenesis of obesity-related asthma have not yet been directly tested but offer an interesting area of future research given the availability of approved GLP-1R agonists for weight loss and ongoing studies of citrulline supplementation in obese asthma, both of which may influence this axis.

Insights from Differential Expression and Methylation of Genes in Obese Asthma

Studies have identified differential expression and methylation of genes in obese asthma compared with nonobese asthma, lending insights into the molecular pathogenesis of obese asthma. Gene expression is a dynamic process, and, notably, obesity itself has been shown to modify expression of genes associated with asthma (178). From these studies, several overrepresented pathways have emerged as potential novel therapeutic targets for obese asthma.

IFN-related Signaling Pathways

Transcriptomic studies of obese asthma have demonstrated that IFN-related signaling pathways are overrepresented in adults with obese asthma compared with nonobese asthma and healthy control subjects and are induced by IFN-stimulated genes, such as IFITM3, IFIT3, OAS2, OAS3, EIF2AK2, MXI, USP18, and GBP3 (179). IFN-related miRNAs have also been shown to be differentially expressed in plasma extracellular vesicles in adults with obese asthma (180). Likewise, functional enrichment analyses of a transcriptome-wide association study of nasal epithelial samples from youth with asthma demonstrated that that IFN-γ production and type-I IFN signaling pathways, including genes such as ISG15, LILRB1, IFI35, RSAD2, and ISG20, were overrepresented among youth with obese asthma compared with those with nonobese asthma (181). Preliminary examination of gene expression in adipose tissue from youth and adolescents with asthma has also demonstrated upregulation of genes involved in IFN signaling pathways in obesity-associated asthma (182). Involvement of the IFN-γ signaling pathway may indicate the CD4⁺ T cells in individuals with obese asthma have been skewed toward T1 polarization (179); these differentially expressed genes may represent novel therapeutic targets for obese asthma.

Rho-GTPase Pathways

Studies have also demonstrated that PAK3 is upregulated in obese compared with nonobese children with asthma (183, 184). PAK3 is in the Rho-GTPase pathway, as are many other differentially expressed genes and differentially methylated CG sites for children with obese asthma, suggesting that Rho-GTPases and their downstream signaling pathways may also be potential novel therapeutic targets for pediatric obesity-related asthma (183, 185). Rho-GTPases modify the immune synapse, which modulates T-helper (T) cell differentiation and influences the differentiation of naive T cells to the T1 phenotype (186) and production of nonatopic cytokines, IFN-γ, and tumor necrosis factor (187). T cells from children with obese asthma have been shown to have uninhibited chemotaxis and be more adherent to obese airway smooth muscle, which was associated with upregulation of genes and proteins associated with airway smooth muscle proliferation and nonatopic T cell activation (188).

CDC42 Pathway

Genes associated with CDC42 (cell division control protein 42 homolog), a specific small Rho-GTPase, were shown to be upregulated in peripheral blood T cells from obese children with asthma. These genes include upstream activators of CDC42, VAV2, and DOCK4, genes that directly interact with CDC42, CDC42EP4, and downstream effectors CDC2BPB, PAK3, and PLD1. Abundance of these CDC42 pathway genes was directly correlated with lower airway obstruction. This observed activation of CDC42-related pathways may explain the differentiation bias toward a Th1 lineage in children with asthma and obesity and may also represent a potential novel therapeutic target for pediatric obese asthma (184).

Integrins

Weighted gene coexpression network analysis of gene expression in whole blood demonstrated enrichment of integrin-related genes, such as ITGA2B, ITGB3, and ITGB5, in adults with obese asthma compared with those with nonobese asthma (189). Integrins anchor airway smooth muscle to the extracellular matrix and play a role in AHR and remodeling (190). The findings were replicated in two independent cohorts of individuals with asthma, one adult and one pediatric, suggesting that integrins could be a potential novel therapeutic target for obese asthma (189).

Conclusions and Future Directions

Obesity-associated asthma is a disease of both childhood and adulthood that constitutes a unique asthma phenotype. Accordingly, phenotype is increasingly considered in asthma treatment decisions. As discussed, there is growing evidence that medications for obesity and metabolic syndrome, such as metformin and GLP-1 antagonists, may also ameliorate asthma incidence and severity in individuals with obesity. Obesity may also play a role in the efficacy of existing asthma therapies, such as asthma biologic therapies, but the preponderance of the evidence suggests that existing asthma biologics are effective regardless of BMI.

Future studies should test if biologics targeting T1/T17 inflammation, believed to play an important role in obesity-associated asthma, could improve asthma outcomes in individuals with obesity-associated asthma. Other potential novel therapeutic targets for obesity-associated asthma that are currently being evaluated include arginine metabolism, nitro-fatty acids, mitochondrial antioxidants, adipose tissue eosinophils, and the GLP-1–arginine–AGE axis. We may also be able to identify therapeutic targets for obesity-associated asthma using insights gained from omics studies; transcriptomic and epigenetic studies to date suggest that that pathways for IFN signaling, Rho-GTPase, CDC42, and integrins are upregulated in obesity-associated asthma.

The heterogeneity and complexity of asthma necessitates precision medicine. Additional studies elucidating the distinct inflammatory pathways characteristic of obesity-associated asthma will continue to facilitate development of effective treatments for this unique asthma phenotype.