Universität zu Köln

Selle, Jaco ORCID: 0000-0002-4981-0931, Dinger, Katharina, Jentgen, Vanessa, Zanetti, Daniela ORCID: 0000-0002-1225-1021, Will, Johannes, Georgomanolis, Theodoros ORCID: 0000-0002-4066-9257, Vohlen, Christina, Wilke, Rebecca, Kojonazarov, Baktybek, Klymenko, Oleksiy, Mohr, Jasmine, Koningsbruggen-Rietschel, Silke, V, Rhodes, Christopher J., Ulrich, Anna, Hirani, Dharmesh, Nestler, Tim, Odenthal, Margarete, Mahabir, Esther, Nayakanti, Sreenath, Dabral, Swati, Wunderlich, Thomas, Priest, James, Seeger, Werner ORCID: 0000-0003-1946-0894, Doetsch, Joerg, Pullamsetti, Soni S. and Alcazar, Miguel A. Alejandre (2022). Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life. Nat. Commun., 13 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

This study shows that maternal and perinatal obesity cause bronchial and vascular smooth muscle cell proliferation through an IL-6-FoxO1 axis, and favor thereby the emergence of bronchial obstruction and pulmonary hypertension later in life. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Selle, Jaco UNSPECIFIED orcid.org/0000-0002-4981-0931 UNSPECIFIED Dinger, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Jentgen, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Zanetti, Daniela UNSPECIFIED orcid.org/0000-0002-1225-1021 UNSPECIFIED Will, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Georgomanolis, Theodoros UNSPECIFIED orcid.org/0000-0002-4066-9257 UNSPECIFIED Vohlen, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Wilke, Rebecca UNSPECIFIED UNSPECIFIED UNSPECIFIED Kojonazarov, Baktybek UNSPECIFIED UNSPECIFIED UNSPECIFIED Klymenko, Oleksiy UNSPECIFIED UNSPECIFIED UNSPECIFIED Mohr, Jasmine UNSPECIFIED UNSPECIFIED UNSPECIFIED Koningsbruggen-Rietschel, Silke, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Rhodes, Christopher J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ulrich, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Hirani, Dharmesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Nestler, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Mahabir, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Nayakanti, Sreenath UNSPECIFIED UNSPECIFIED UNSPECIFIED Dabral, Swati UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunderlich, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Priest, James UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeger, Werner UNSPECIFIED orcid.org/0000-0003-1946-0894 UNSPECIFIED Doetsch, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Pullamsetti, Soni S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alcazar, Miguel A. Alejandre UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-687037
DOI:	10.1038/s41467-022-31655-z
Journal or Publication Title:	Nat. Commun.
Volume:	13
Number:	1
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTRAUTERINE GROWTH RESTRICTION; BODY-MASS INDEX; ARTERIAL-HYPERTENSION; TRANSCRIPTION FACTOR; LUNG-FUNCTION; ASTHMA; IL-6; PREVENTION; INFLAMMATION; PATHOGENESIS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68703