Impact of obesity and ovariectomy on respiratory function in female mice

https://doi.org/10.1016/j.resp.2021.103775Get rights and content

Highlights

  • Influences of obesity and ovarectomy on the lung and airway resistance.

  • Airway and lung vessels remodeling are affected in obese ovariectomized mice.

  • Estrogen receptor-β can play a significate role in the lung.

Abstract

Obesity and the corresponding variations in female sex hormones are associated with severe lung disease. We determined the potential effects of obesity and sex hormones in female mice by investigating changes in lung structure and respiratory function in an obesity model induced by postnatal overnutrition. Obese female mice exhibited pronounced weight gain, abdominal fat accumulation and collagen type I deposition in the airways. However, neither elastic tissue nor estrogen receptors-α/-β were affected in obese female mice after ovariectomy or sham-operated mice. Bronchoconstriction in response to methacholine challenge in obese sham-operated mice was higher than in the obese group after ovariectomy. Our results suggest that the coexistence of obesity and ovariectomy impacted on respiratory system and airway resistance (attenuates bronchoconstriction after methacholine), on collagen I deposition and on airway estrogen β-receptors of mice.

Introduction

Obesity is characterized by excessive and abnormal fat accumulation, which has a significant deleterious effect on health (Melo et al., 2014; Zammit et al., 2010). The WHO estimates approximately 39 % of the global population as overweight and approximately 13% as obese (WHO, 2020). The list of comorbidities associated with obesity is extensive and accounts for ranking of cause of death globally. This list includes diabetes, obstructive sleep apnea, hypertension, hormonal dysfunction, and lung impairment (Mifflin and Strack, 2007; Romero-Corral et al., 2008; Salome et al., 2010).

The lungs are significantly affected in obese patients, with a higher incidence of asthma development, emboli, and pneumonia observed in women (Grassi et al., 2020; Mancuso, 2010; Orfanos et al., 2018). Asthmatic/obese patients present with a reduction in lung volume by means of limited thoracic expansion, resulting in impairment of ventilation/perfusion rates and abnormalities in blood oxygen levels (Grassi et al., 2020; Özbey et al., 2019). Obese patients also demand a higher recruitment of respiratory muscles and sometimes present with enhanced airway resistance (Orfanos et al., 2018).

As previously reported, asthmatic/obese patients also present a reduction in lung volume by means of limited thoracic expansion, resulting in impairment of ventilation/perfusion rates and abnormalities in blood oxygen levels (Grassi et al., 2020; Orfanos et al., 2018; Özbey et al., 2019). Obese patients also demand a higher recruitment of respiratory muscles and sometimes show enhanced airway resistance (Orfanos et al., 2018; Thais Fantozzi et al., 2018).

Clinical studies have indicated that there is a strong influence of sex hormones on lung function (Carey et al., 2007; Townsend et al., 2012). Equivalently, the severity of chronic inflammatory airway disease is exacerbated by sex (Carey et al., 2007; Iñigo et al., 2020; Nelson et al., 2018). Furthermore, existing evidence supports the idea of sex differences in the pathophysiology and severity of asthma (Bonds and Midoro-Horiuti, 2013; Keselman et al., 2017; Zein et al., 2015; Zein and Erzurum, 2015). It has been reported that lung function could change due to various hormonal variations such as menstrual cycle phase and pregnancy (Carey et al., 2007). Because of this, asthma prevalence is higher in women during puberty and menopause than in men (Bonds and Midoro-Horiuti, 2013; Townsend et al., 2012). These effects show a strong correlation with expression of the estrogen receptor (ER) in the lung and airways, which are very important for alveolar development and bronchial responsiveness (Carey et al., 2007; Kalidhindi et al., 2019; Massaro et al., 2007; Massaro and Massaro, 2004).

Nevertheless, obesity has been focus of investigation of several studies in male, still poorly studied in female. In this context, our studies focus on investigating the detrimental effects of obesity on lung function in female mice. Specifically, the goal of the current study is to investigate the role of association of the obesity and the ovariectomy on respiratory function, remodeling and lung expression of the estrogen receptors-α/-β.

Section snippets

Animals and experimental outline

Swiss Webster mice were used in the present study, and were obtained from the Central Animal Facility of the Federal University of Alfenas (Alfenas, MG, Brazil). All animal experimentation was consistent with the National Institutes of Health guidelines and approved by the institutional animal care and use committee (protocol number 27/2018). Mice were housed in a temperature-controlled chamber at 22 ± 2 °C and light/dark cycle-controlled (12:12 h) with ad libitum access to water and food.

Obesity model, group and time design

Obesity model confirmation

We characterized our obesity model by measuring body mass, abdominal fat, and biochemical parameters (Data not shown). As expected, obese mice had higher abdominal fat indices (Obese sham: 1.88 ± 0.04 and Obese Ovx: 2.66 ± 0.22 vs. control sham: 0.77 ± 0.05 g; p < 0.001; F(3,26) = 22.634; One-way ANOVA). Mice that underwent the Ovx procedure alone had increased abdominal fat (Control Ovx: 1.31 ± 0.04 g vs. control sham: 0.77 ± 0.05 g; p < 0.001; F(3,26) = 22.634; One-way ANOVA). As a

Discussion

Obesity is the focus of many studies, given its high incidence throughout the world. Many of these studies aim to investigate the role of different comormidites in obese patients, as there are a significant number of contributing factors. Estrogen could provide a protective effect to some of these comorbidities through its purported anti-inflammatory properties (Keselman et al., 2017; Martínez-Chacón et al., 2018). This concept led us to believe that estrogen levels may play a role during

Conclusion

We have shown that obese female Ovx mice develop an attenuated response to MCh, as determined by an increase in total resistance and airway resistance. Moreover, a reduction in type I collagen in the lungs (airway and vessels) and reduced ER-β expression in the airways was observed in these coexisting conditions. These results suggest that obesity and estrogen (and the association of both conditions) have an important role in driving the morphology and function of the lungs.

Experimental limitations

Some limitations could have an impact on these experiments and the interpretation of the results. First, obesity was induced by a postnatal over nutrition protocol; thus, other obesity experimental models, such as genetic or diet-induced obesity models may not be extrapolated. Second, further experiments should be performed to understand how inflammatory cells are recruited. Futhermore, it is important to determine the impacts of pro-inflammatory cytokynes release in this model, including how

Author contributions

Conceptualization, R.S.; Methodology, A.C.R.L., B.Z., R.S., Investigation, A.C.R.L., B.Z., Y.J.C.C., T.M.V., R.S.; formal analysis, A.C.R.L., B.Z., L.M.O., R.S.; writing-review and editing, A.C.R.L., B.Z., L.J.S., L.M.O., R.S.; supervision, R.S.

Declaration of Competing Interest

We declare no financial conflicts of interest.

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