Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

Jaco Selle, Katharina Dinger, Vanessa Jentgen, Daniela Zanetti, Johannes Will, Theodoros Georgomanolis, Christina Vohlen, Rebecca Wilke, Baktybek Kojonazarov, Oleksiy Klymenko, Jasmine Mohr, Silke v. Koningsbruggen-Rietschel, Christopher J. Rhodes, Anna Ulrich, Dharmesh Hirani, Tim Nestler, Margarete Odenthal, Esther Mahabir, Sreenath Nayakanti, Swati Dabral, Thomas Wunderlich, James Priest, Werner Seeger, Jörg Dötsch, Soni S. Pullamsetti and Miguel A. Alejandre Alcazar ()
Additional contact information
Jaco Selle: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Katharina Dinger: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Vanessa Jentgen: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Daniela Zanetti: Stanford University School of Medicine
Johannes Will: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Theodoros Georgomanolis: Faculty of Medicine and University Hospital Cologne, Cologne Center for Genomics (CCG), University of Cologne
Christina Vohlen: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Rebecca Wilke: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Baktybek Kojonazarov: University of Giessen and Marburg Lung Centre (UGMLC), Member of the German Centre for Lung Research (DZL)
Oleksiy Klymenko: University of Giessen and Marburg Lung Centre (UGMLC), Member of the German Centre for Lung Research (DZL)
Jasmine Mohr: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Silke v. Koningsbruggen-Rietschel: Faculty of Medicine and University Hospital Cologne, Pediatric Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Christopher J. Rhodes: Imperial College London
Anna Ulrich: Imperial College London
Dharmesh Hirani: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne
Tim Nestler: Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne
Margarete Odenthal: Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne (CMMC), University of Cologne
Esther Mahabir: Faculty of Medicine and University Hospital Cologne, Comparative Medicine, Center for Molecular Medicine Cologne (CMMC), University of Cologne
Sreenath Nayakanti: Member of the German Center for Lung Research (DZL)
Swati Dabral: Member of the German Center for Lung Research (DZL)
Thomas Wunderlich: Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne (CMMC), University of Cologne
James Priest: Stanford University School of Medicine
Werner Seeger: University of Giessen and Marburg Lung Centre (UGMLC), Member of the German Centre for Lung Research (DZL)
Jörg Dötsch: Faculty of Medicine and University Hospital Cologne, Department of Pediatric and Adolescent Medicine, University of Cologne
Soni S. Pullamsetti: University of Giessen and Marburg Lung Centre (UGMLC), Member of the German Centre for Lung Research (DZL)
Miguel A. Alejandre Alcazar: Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics–Experimental Pulmonology, Department of Pediatric and Adolescent Medicine, University of Cologne

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Obesity is a pre-disposing condition for chronic obstructive pulmonary disease, asthma, and pulmonary arterial hypertension. Accumulating evidence suggests that metabolic influences during development can determine chronic lung diseases (CLD). We demonstrate that maternal obesity causes early metabolic disorder in the offspring. Here, interleukin-6 induced bronchial and microvascular smooth muscle cell (SMC) hyperproliferation and increased airway and pulmonary vascular resistance. The key anti-proliferative transcription factor FoxO1 was inactivated via nuclear exclusion. These findings were confirmed using primary SMC treated with interleukin-6 and pharmacological FoxO1 inhibition as well as genetic FoxO1 ablation and constitutive activation. In vivo, we reproduced the structural and functional alterations in offspring of obese dams via the SMC-specific ablation of FoxO1. The reconstitution of FoxO1 using IL-6-deficient mice and pharmacological treatment did not protect against metabolic disorder but prevented SMC hyperproliferation. In human observational studies, childhood obesity was associated with reduced forced expiratory volume in 1 s/forced vital capacity ratio Z-score (used as proxy for lung function) and asthma. We conclude that the interleukin-6-FoxO1 pathway in SMC is a molecular mechanism by which perinatal obesity programs the bronchial and vascular structure and function, thereby driving CLD development. Thus, FoxO1 reconstitution provides a potential therapeutic option for preventing this metabolic programming of CLD.

Date: 2022
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DOI: 10.1038/s41467-022-31655-z

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