Fig. 3.

A diagram of the proposed pathway for induction of altered glucose homeostasis in the offspring of rats fed a protein-restricted (PR) diet during pregnancy. A full explanation is given in the text. (a) Glucocorticoid receptor (GR) expression is silenced in the early embryo in cells destined to become hepatocytes by the activities of DNA methyltransferases (Dnmt) 3a and 3b. (b) In the offspring of rats fed a PR diet, 1-carbon metabolism is impaired either as a direct consequence of the restricted diet or by increased glucocorticoid exposure. This down-regulates Dnmt1 expression (c). Lower Dnmt1 expression results in a impaired capacity to methylate hemimethylated DNA during mitosis (d). After sequential mitotic cycles, this results in hypomethylation of the GR promoter and loss of epigenetic memory of gene silencing, such that, in the liver of the adult offspring, expression of GR is induced in cells which do not express GR in control animals. The increased expression of GR is facilitated by lower binding and expression of methyl CpG binding protein (MeCP)-2 and reduced recruitment of the histone deactylase (HDAC) / histone methyltransferase (HMT) complex, resulting in higher levels of histone modifications which permit transcription. (e) This results in increased phosphoenolpyruvate carboxykinase (PEPCK) expression and increased gluconeogenesis.