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Kammel, A.* ; Saussenthaler, S.* ; Jähnert, M.* ; Jonas, W.* ; Stirm, L.* ; Hoeflich, A.* ; Staiger, H.* ; Fritsche, A.* ; Häring, H.-U.* ; Joost, H.G.* ; Schürmann, A.* ; Schwenk, R.W.*

Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice.

Hum. Mol. Genet., DOI: 10.1093/hmg/ddw121 (2016)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Obesity and ectopic fat disposition are risk factors for metabolic disease. Recent data indicate that IGFBP2 expression in liver is epigenetically inhibited during hepatic steatosis. The aim of this study was to investigate if epigenetic de-regulation of hepatic Igfbp2 occurs already early in life and is associated with increased risk for diet-induced obesity (DIO) during adolescence. Male C57BL/6J mice received a high-fat diet. After 3 weeks on this diet (age of 6 weeks), DIO-susceptible (responder, Resp) and DIO-resistant (non-responder, nResp) mice were identified by early weight gain. At the age of 6 weeks, Resp mice exhibited elevated blood glucose (p < 0.05), plasma insulin (p < 0.01), HOMA-IR and leptin/adiponectin ratio, whereas liver triglycerides were identical but significantly increased (p < 0.01) in Resp mice at 20 weeks of age. Igfbp2 expression was reduced in young Resp compared with nResp mice (p < 0.01), an effect that correlated with elevated DNA methylation of intronic CpG2605 (p < 0.01). The epigenetic inhibition of Igfbp2 was stable over time and preceded DIO and hepatosteatosis in adult mice. In vitro studies demonstrated that selective methylation of CpG2605 significantly reduced reporter activity by ∼85%, indicating that Igfbp2 expression is modulated by methylation. In human whole blood cells, methylation of IGFBP2 at the homologous CpG site was increased in obese men with impaired glucose tolerance. In conclusion, our data show that increased methylation of hepatic Igfbp2 during infancy predicts the development of fatty liver later in life and is linked to deterioration of glucose metabolism.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2016
HGF-reported in Year 0
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Publisher Oxford University Press
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502400-001
PubMed ID 27126637
DOI 10.1093/hmg/ddw121
Erfassungsdatum 2016-05-24
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