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:
CreatorsEmailORCIDORCID Put Code
Selle, JacoUNSPECIFIEDorcid.org/0000-0002-4981-0931UNSPECIFIED
Dinger, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jentgen, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zanetti, DanielaUNSPECIFIEDorcid.org/0000-0002-1225-1021UNSPECIFIED
Will, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Georgomanolis, TheodorosUNSPECIFIEDorcid.org/0000-0002-4066-9257UNSPECIFIED
Vohlen, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilke, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kojonazarov, BaktybekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klymenko, OleksiyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohr, JasmineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koningsbruggen-Rietschel, Silke, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rhodes, Christopher J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ulrich, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hirani, DharmeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nestler, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahabir, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nayakanti, SreenathUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dabral, SwatiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Priest, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, WernerUNSPECIFIEDorcid.org/0000-0003-1946-0894UNSPECIFIED
Doetsch, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pullamsetti, Soni S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alcazar, Miguel A. AlejandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
INTRAUTERINE GROWTH RESTRICTION; BODY-MASS INDEX; ARTERIAL-HYPERTENSION; TRANSCRIPTION FACTOR; LUNG-FUNCTION; ASTHMA; IL-6; PREVENTION; INFLAMMATION; PATHOGENESISMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68703

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