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.

Keywords: obesity; obesity-related asthma; treatments.

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.

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.

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.