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

Abstract

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.

Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

“…Interspersed between these cells are goblet cells, the major secretory cells in the apical layer of the large airways which produce highly hydrated mucus that is primarily comprised of mucin glycoproteins (Figure 2B). 4,21,55 Hyperplasia of goblet cells and mucus hypersecretion alter the rheological properties of mucus and are a major disease feature of asthma and COPD 4,56‐59 …”

“…There is less evidence of interactions between dietary lipids, the microbiome and lung mucus barrier in healthy states. Although mice fed HFDs have altered GI microbiome composition and develop respiratory inflammation, histopathology and impaired lung function, they do not have altered lung mucus production without another stimulus such as in disease models 57,90,133 . More detailed analysis of mucus composition and characterization of the respiratory microbiome would provide further insights.…”

Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates

“…1) consistent with the infiltrative cardiovascular diseases of the whole heart 50 , characterized by significant reduction in EF and fractional shortening (systolic dysfunction), wider QRS, shortened QT(c) interval, increased LVDP, LVSP, EDV, ESV, and LV mass, and decreased +dp/dt max, -dp/dt max ( Table 1). It is known that high-fat diet negatively affects multiple organs and tissues such as the aorta 67 , heart 68 , lungs 69 , livers 70 , brain 71 , kidneys 72 , and pancreas 73 . Consistent with the previous findings, we observed lipid accumulation in the aorta, arteriopathy in the aorta, brain, lung as well as other major organs, vacuolation in the liver, hyperplasia in the pancreatic islets, mononuclear cells infiltration, and glomerulopathy in the kidneys in some of the HF NHPs treated with high-fat diet.…”

Insights into the Role of Bioactive Food Ingredients and the Microbiome in Idiopathic Pulmonary Fibrosis

“…In mice, neonatal overfeeding induces obesity in adulthood, and worsens airway hyperresponsiveness to methacholine, highlighted by higher amounts of collagen accumulated surrounding the bronchi and lung TGF-β1 expression [ 40 ]. Such hyperresponsiveness is also observed when adult mice are exposed to a high-fat diet [ 41 ]. The higher circulating insulin level exhibited by adult mice fed a high-fat diet seems to be the agent that enhances TGF-β1 expression in the bronchial epithelium, pointing to insulin resistance as an important player in the development of lung fibrosis.…”

“…The exposure to diets rich in lipids triggers the occurrence of pulmonary fibrosis per se [ 42 , 43 ] and worsens the airway responsiveness to a challenging agent [ 40 , 41 ], supporting a potential role for dietary lipids as a direct causative agent of pulmonary fibrosis. The involvement of dietary lipids and lipid handling is reinforced by the fact that alterations in enzymes involved in lipid metabolism exacerbates pulmonary fibrosis [ 8 ], and that IPF patients present a decreased sphingolipid metabolism and mitochondrial β-oxidation capacity [ 44 ].…”