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Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice
Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis wheth...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144113/ https://www.ncbi.nlm.nih.gov/pubmed/35628414 http://dx.doi.org/10.3390/ijms23105609 |
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author | Kasper, Philipp Selle, Jaco Vohlen, Christina Wilke, Rebecca Kuiper-Makris, Celien Klymenko, Oleksiy Bae-Gartz, Inga Schömig, Charlotte Quaas, Alexander Schumacher, Björn Demir, Münevver Bürger, Martin Lang, Sonja Martin, Anna Steffen, Hans-Michael Goeser, Tobias Dötsch, Jörg Alcazar, Miguel A. Alejandre |
author_facet | Kasper, Philipp Selle, Jaco Vohlen, Christina Wilke, Rebecca Kuiper-Makris, Celien Klymenko, Oleksiy Bae-Gartz, Inga Schömig, Charlotte Quaas, Alexander Schumacher, Björn Demir, Münevver Bürger, Martin Lang, Sonja Martin, Anna Steffen, Hans-Michael Goeser, Tobias Dötsch, Jörg Alcazar, Miguel A. Alejandre |
author_sort | Kasper, Philipp |
collection | PubMed |
description | Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity. |
format | Online Article Text |
id | pubmed-9144113 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91441132022-05-29 Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice Kasper, Philipp Selle, Jaco Vohlen, Christina Wilke, Rebecca Kuiper-Makris, Celien Klymenko, Oleksiy Bae-Gartz, Inga Schömig, Charlotte Quaas, Alexander Schumacher, Björn Demir, Münevver Bürger, Martin Lang, Sonja Martin, Anna Steffen, Hans-Michael Goeser, Tobias Dötsch, Jörg Alcazar, Miguel A. Alejandre Int J Mol Sci Article Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity. MDPI 2022-05-17 /pmc/articles/PMC9144113/ /pubmed/35628414 http://dx.doi.org/10.3390/ijms23105609 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kasper, Philipp Selle, Jaco Vohlen, Christina Wilke, Rebecca Kuiper-Makris, Celien Klymenko, Oleksiy Bae-Gartz, Inga Schömig, Charlotte Quaas, Alexander Schumacher, Björn Demir, Münevver Bürger, Martin Lang, Sonja Martin, Anna Steffen, Hans-Michael Goeser, Tobias Dötsch, Jörg Alcazar, Miguel A. Alejandre Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice |
title | Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice |
title_full | Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice |
title_fullStr | Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice |
title_full_unstemmed | Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice |
title_short | Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice |
title_sort | perinatal obesity induces hepatic growth restriction with increased dna damage response, senescence, and dysregulated igf-1-akt-foxo1 signaling in male offspring of obese mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144113/ https://www.ncbi.nlm.nih.gov/pubmed/35628414 http://dx.doi.org/10.3390/ijms23105609 |
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