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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  &lt; 0.05), plasma insulin ( p  &lt; 0.01), HOMA-IR and leptin/adiponectin ratio, whereas liver triglycerides were identical but significantly increased ( p  &lt; 0.01) in Resp mice at 20 weeks of age.  Igfbp2  expression was reduced in young Resp compared with nResp mice ( p  &lt; 0.01), an effect that correlated with elevated DNA methylation of intronic CpG 2605  ( p  &lt; 0.01). The epigenetic inhibition of  Igfbp2  was stable over time and preceded DIO and hepatosteatosis in adult mice.  In vitr o studies demonstrated that selective methylation of CpG 2605  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.

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