Obesity elicits a unique metabolomic signature in human airway smooth muscle cells

Author:

Xu Shengjie12,Karmacharya Nikhil2,Cao Gaoyuan2,Guo Changjiang1,Gow Andrew1ORCID,Panettieri Reynold A.123ORCID,Jude Joseph A.123ORCID

Affiliation:

1. Department of Pharmacology and Toxicology, The Joint Graduate Program in Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey

2. Rutgers Institute for Translational Medicine and Science, Rutgers, The State University of New Jersey, New Brunswick, New Jersey

3. Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey

Abstract

Obesity can aggravate asthma by enhancing airway hyperresponsiveness (AHR) and attenuating response to treatment. However, the precise mechanisms linking obesity and asthma remain unknown. Human airway smooth muscle (HASM) cells exhibit amplified excitation-contraction (EC) coupling and force generation in obesity. Therefore, we posit that airway smooth muscle (ASM) cells obtained from obese donors manifest a metabolomic phenotype distinct from that of nonobese donor cells and that a differential metabolic phenotype, at least in part, drives enhanced ASM cell EC coupling. HASM cells derived from age-, sex-, and race-matched nonobese [body mass index (BMI) ≤ 24.9 kg·m−2] and obese (BMI ≥ 29.9 kg·m−2) lung donors were subjected to unbiased metabolomic screening. The unbiased metabolomic screening identified differentially altered metabolites linked to glycolysis and citric acid cycle in obese donor-derived cells compared with nonobese donor cells. The Seahorse assay measured the bioenergetic profile based on glycolysis, mitochondrial respiration, palmitate oxidation, and glutamine oxidation rates in HASM cells. Glycolytic rate and capacity were elevated in obese donor-derived HASM cells, whereas mitochondrial respiration, palmitate oxidation, and glutamine oxidation rates were comparable between obese and nonobese groups. PFKFB3 mRNA and protein expression levels were also elevated in obese donor-derived HASM cells. Furthermore, pharmacological inhibition of PFKFB3 attenuated agonist-induced myosin light chain (MLC) phosphorylation in HASM cells derived from obese and nonobese donors. Our findings identify elevated glycolysis as a signature metabolic phenotype of obesity and inhibition of glycolysis attenuates MLC phosphorylation in HASM cells. These findings identify novel therapeutic targets to mitigate AHR in obesity-associated asthma.

Funder

HHS | NIH | NHLBI | NHLBI Division of Intramural Research

HHS | NIH | National Center for Advancing Translational Sciences

Robert Wood Johnson Foundation

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Metabolomics in Animal Models of Bronchial Asthma and Its Translational Importance for Clinics;International Journal of Molecular Sciences;2023-12-29

2. Influence of obesity on the tone of bronchial smooth muscles in rats;Acta Biomedica Scientifica;2023-07-11

3. Crosstalk between CD4+ T Cells and Airway Smooth Muscle in Pediatric Obesity-related Asthma;American Journal of Respiratory and Critical Care Medicine;2023-02-15

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