title: Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice.
abstract: 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 CpG2605significantly 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.
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kammel
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Saussenthaler
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Jähnert
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Wenke
authors.initials: W
authors.lastname: Jonas
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Stirm
authors.affiliation: Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeflich
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany schuermann@dife.de.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schwenk
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose; D019175:DNA Methylation / Q000235:genetics*; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2