Insulin resistance mediates high-fat diet-induced pulmonary fibrosis and airway hyperresponsiveness through the TGF-β1 pathway

• Published in: Experimental & molecular medicine Vol. 51; no. 5; pp. 1 - 12
• Main Authors: Park, Yoon Hee, Oh, Eun Yi, Han, Heejae, Yang, Misuk, Park, Hye Jung, Park, Kyung Hee, Lee, Jae-Hyun, Park, Jung-Won
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2019; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/1; 13/51; 631/250; 64/60; 692/308/1426; Alveoli; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Bronchus; Diet, High-Fat - adverse effects; Epithelium; Fibrosis; Glucose tolerance; High fat diet; Hyperplasia; Immunological tolerance; Inflammation; Insulin; Insulin Resistance; Interleukin 5; Intranasal administration; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lung - metabolism; Lung - pathology; Lung diseases; Macrophages; Male; Medical Biochemistry; Methacholine; Mice, Inbred C57BL; Molecular Medicine; Obesity; Ovalbumin; Pulmonary fibrosis; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Respiratory tract; Signal Transduction; Stem Cells; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-019-0258-7

Prior studies have reported the presence of lung fibrosis and enhanced airway hyperresponsiveness (AHR) in mice with high-fat-diet (HFD)-induced obesity. This study evaluated the role of TGF-β1 in HFD-induced AHR and lung fibrosis in a murine model. We generated HFD-induced obesity mice and performed glucose and insulin tolerance tests. HFD mice with or without ovalbumin sensitization and challenge were also treated with an anti-TGF-β1 neutralizing antibody. AHR to methacholine, inflammatory cells in the bronchoalveolar lavage fluid (BALF), and histological features were evaluated. Insulin was intranasally administered to normal diet (ND) mice, and in vitro insulin stimulation of BEAS-2b cells was performed. HFD-induced obesity mice had increased insulin resistance, enhanced AHR, peribronchial and perivascular fibrosis, and increased numbers of macrophages in the BALF. However, they did not have meaningful eosinophilic or neutrophilic inflammation in the lungs compared with ND mice. The HFD enhanced TGF-β1 expression in the bronchial epithelium, but we found no differences in the expression of interleukin (IL)−4 or IL-5 in lung homogenates. Administration of the anti-TGF-β1 antibody attenuated HFD-induced AHR and lung fibrosis. It also attenuated goblet cell hyperplasia, but did not affect the AHR and inflammatory cell infiltration induced by OVA challenge. The intranasal administration of insulin enhanced TGF-β1 expression in the bronchial epithelium and lung fibrosis. Stimulating BEAS-2b cells with insulin also increased TGF-β1 production by 24 h. We concluded that HFD-induced obesity-associated insulin resistance enhances TGF-β1 expression in the bronchial epithelium, which may play an important role in the development of lung fibrosis and AHR in obesity. Obesity: A trigger for asthma onset Insulin resistance may be an important causative factor underlying the increased risk of asthma and other respiratory issues in obese individuals. Obesity doubles the likelihood of developing asthma, with symptoms that are more difficult to control than in non-obese patients. The connection between these conditions is poorly understood, but researchers led by Jung-Won Park, Yonsei University College of Medicine, Seoul, South Korea, have identified a potential mechanism. They demonstrated that a signaling molecule called TGF-β1 contributes to airway sensitivity and tissue scarring in a mouse model of diet-induced obesity. Subsequent experiments showed that treatment with insulin also gives rise to increased TGF-β1 production in the mouse lung. Since insulin resistance is a common feature of obesity, resulting in abnormally high levels of circulating insulin, this could also account for the increased risk of respiratory problems.