Universität zu Köln

Kasper, Philipp ORCID: 0000-0002-6218-2239, Selle, Jaco ORCID: 0000-0002-4981-0931, Vohlen, Christina, Wilke, Rebecca, Kuiper-Makris, Celien ORCID: 0000-0002-7940-9612, Klymenko, Oleksiy, Bae-Gartz, Inga ORCID: 0000-0002-4061-503X, Schoemig, Charlotte, Quaas, Alexander, Schumacher, Bjorn, Demir, Munevver ORCID: 0000-0002-7050-797X, Buerger, Martin, Lang, Sonja, Martin, Anna, Steffen, Hans-Michael ORCID: 0000-0001-6562-3549, Goeser, Tobias, Doetsch, Jorg and Alcazar, Miguel A. Alejandre (2022). 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. Int. J. Mol. Sci., 23 (10). BASEL: MDPI. ISSN 1422-0067

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Abstract

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 (gamma H2AX), (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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kasper, Philipp UNSPECIFIED orcid.org/0000-0002-6218-2239 UNSPECIFIED Selle, Jaco UNSPECIFIED orcid.org/0000-0002-4981-0931 UNSPECIFIED Vohlen, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Wilke, Rebecca UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuiper-Makris, Celien UNSPECIFIED orcid.org/0000-0002-7940-9612 UNSPECIFIED Klymenko, Oleksiy UNSPECIFIED UNSPECIFIED UNSPECIFIED Bae-Gartz, Inga UNSPECIFIED orcid.org/0000-0002-4061-503X UNSPECIFIED Schoemig, Charlotte UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaas, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Bjorn UNSPECIFIED UNSPECIFIED UNSPECIFIED Demir, Munevver UNSPECIFIED orcid.org/0000-0002-7050-797X UNSPECIFIED Buerger, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Lang, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Martin, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Steffen, Hans-Michael UNSPECIFIED orcid.org/0000-0001-6562-3549 UNSPECIFIED Goeser, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Doetsch, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Alcazar, Miguel A. Alejandre UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-678253
DOI:	10.3390/ijms23105609
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	23
Number:	10
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MATERNAL OBESITY; LIVER-REGENERATION; PROLIFERATION; EXPRESSION; HEALTH Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67825