Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone. It has been reported that FGF21 transcription levels increase in murine liver after either fasting or exposure to a ketogenic diet. The developmental origins of adult disease hypothesis postulates that metabolic and growth perturbations in utero can cause susceptibility to adult dieases, In a transgenerational rat model of intrauterine growth restriction (IUGR) we have demonstrated that second-generation rats born small for gestational age will develop obesity and metabolic disorders in adulthood; this morbidity can be prevented with supplementation of nutrients along the 1-carbon pathway (ENS diet). In order to better understand the molecular physiologic basis for these observations, we studied liver tissue from the F2 generation at both day 21 (d21) and day 160 (d160). Employing standard assays for IGF1 expression and differential methylation of its promoter, we have previously demonstrated that IGF1 is epigenetically downregulated in formerly IUGR animals destined to become obese in adult life. In these studies, we have extended our characterization to FGF21, an upstream regulator of the IGF1 signaling cascade implicated as a mitigater in the development of diabetes. We observed that among females, prevention of adult metabolic disease in IUGR lineage F2 exposed and later fed an ENS diet (Teklad8640+folic acid/betaine, choline/B12/L-methionine/L-arginine/zinc) had an associative significant increase in FGF21 expression by d160 (3.419 fold, p<0.001). This dramatic induction differed by gender, as male rats under the same conditions demonstrated no significant change in FGF21 expression at d160 (0.469-fold, p=.132). Of interest, when we examined expression of FGF21 at d21, prior to the onset of adult morbidity, we observed the inverse association to be true: relative to their non-IUGR lineage counterparts on a regular diet (Teklad8640), FGF21 expression among males at d21 was modestly affected (3.419 fold, p .087), with no significant affect among females . Taken together, these findings by virtue of gender bias suggested to us that sex hormones may be influencing FGF21 expression in our rat model. To formally explore this possibility, we examined expression of FGF23, FRAG1, FGF receptor, and βklotho with QPCR. Significant increases of βklotho and FRAG1 expression accompanied our FGF21 expression observations d160 rats (p<0.001). In summary, while recent reports would suggeset that FGF21 mitigates adult metabolic disease, our observations in a transgener model indicate that FGF21 expression is altered in a gender specific, methyl donor diet amenable fashion. Research supported by NIH Director New Innovator Pioneer Award DP2120OD001500-01(K.A.T) and NICHD-March of Dimes reproductive Scientist Development Program (K.A.T). (poster) Copyright 2010 by The Society for the Study of Reproduction. Copyright 2010 by The Society for the Study of Reproduction.