{"doi":"10.1111/cea.14252","title":"Dual GIPR and GLP‐1R agonist tirzepatide inhibits aeroallergen‐induced allergic airway inflammation in mouse model of obese asthma","abstract":"Nearly 1 in 2 adults is projected to be obese by 2030 in the United States.1 Obesity is a risk factor for asthma and is associated with severe, uncontrolled disease. However, there are no pharmacologic therapeutics specifically designated for obese patients with asthma in the current asthma treatment guidelines from the National Heart, Lung, and Blood Institute of the United States National Institutes of Health. In the past two decades, incretin mimetic drugs such as glucagon like peptide-1 receptor (GLP-1R) agonists have been approved for type 2 diabetes. Tirzepatide, a dual gastric inhibitory peptide receptor (GIPR) and GLP-1R agonist, demonstrated greater glycemic control and weight loss than with selective GLP-1R agonists in clinical trials,2, 3 and was approved as a drug for type 2 diabetes by the U.S. Food and Drug Administration in May 2022. Our group previously reported that GLP-1R agonist treatment using liraglutide significantly decreased aeroallergen-induced innate allergic inflammation and was associated with a reduction in airway IL-33 release and decreased group 2 innate lymphoid cell (ILC2) activation in lean and obese mouse models.4, 5 Therefore, we hypothesized that tirzepatide treatment is more effective to decrease allergic inflammation in an obese mouse model compared with either a GLP-1R or GIP single selective receptor agonist treatment. To test this hypothesis, we used a [D-Ala2]-GIP (GIPR agonist), semaglutide (GLP-1R agonist), tirzepatide (the dual agonist), or vehicle to treat polygenic obese TALLYHO Jng/J (TALLYHO) mice. Additional information about study methods and findings are available in the following online repository (https://doi.org/10.5281/zenodo.7190225). First, we evaluated the effects of the incretin mimetic drugs on metabolic changes in TALLYHO mice. The drug treatment protocol is shown in Figure 1A. [D-Ala2]-GIP treatment did not change the bodyweight compared with the vehicle-treated group. Semaglutide treatment temporally decreased the bodyweight 24 h after each treatment, but the weight loss resolved within 48 h after each treatment. In contrast, tirzepatide treatment resulted in a significant decrease of bodyweight compared with the vehicle treatment (Figure 1B). Semaglutide and tirzepatide, but not [D-Ala2]-GIP decreased serum glucose levels after fasting for 6 h and glucose tolerance after intraperitoneal injection of dextrose (Figure 1C,D). Further, tirzepatide treatment improved glucose tolerance compared with semaglutide treatment (Figure 1C). The area under the curve (AUC) of a glucose tolerance test (GTT) was significantly decreased by semaglutide and tirzepatide treatment compared with vehicle treatment (Figure 1E). The obesity biomarker, serum leptin, was significantly decreased by tirzepatide treatment, but not the other drug treatment (Figure 1F). Taken together, tirzepatide showed robust improvements in glycemic control and bodyweight in polygenic obese mice. Next, we measured the protein levels of inflammatory cytokines and chemokines in lung homogenates from Alternaria alternata extract (Alt-Ext)- or PBS-challenged mice treated with incretin mimetic drugs. The experimental design is shown in Figure 2A. Alt-Ext-challenge significantly increased the protein expression of IL-5, IL-6, IL-13, IL-33, eotaxin (CCL11), eotaxin-2 (CCL24), TARC (CCL17) and MDC (CCL22) in the lung homogenates compared with PBS-challenge (Figure 2B–I). Alt-Ext-induced IL-5 and IL-13 were significantly decreased in the tirzepatide treatment group compared with the vehicle treatment group (Figure 2B,C), but there was no significant difference between tirzepatide and either the [D-Ala2]-GIP or semaglutide treatment group. IL-6, IL-33, CCL11, CCL17, CCL22 and CCL24 were significantly decreased in the semaglutide and tirzepatide treatment groups, but not in the [D-Ala2]-GIP group, compared with vehicle treatment group (Figure 2D–I). Tirzepatide treatment caused a significant reduction of Alt-Ext-induce","journal":"Clinical & Experimental Allergy","year":2022,"id":259253,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":471688,"name":"Jian Zhang","orcid":"0000-0001-7217-0111","position":1,"is_corresponding":false},{"id":455632,"name":"Richard L. Printz","orcid":null,"position":2,"is_corresponding":false},{"id":289419,"name":"Dawn C. Newcomb","orcid":"0000-0003-2592-9433","position":3,"is_corresponding":false},{"id":263307,"name":"Katherine N. Cahill","orcid":"0000-0002-8549-1835","position":4,"is_corresponding":false},{"id":264402,"name":"Kevin D. Niswender","orcid":"0000-0001-6994-8738","position":5,"is_corresponding":false},{"id":290007,"name":"R. Stokes Peebles","orcid":"0000-0002-1429-7875","position":6,"is_corresponding":false},{"id":715523,"name":"Shinji Toki","orcid":"0000-0003-4379-9118","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T00:25:47.305414Z","pmid":"36377605","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}