Protein restriction during pregnancy affects maternal liver lipid metabolism and fetal brain lipid composition in the rat. Am J Physiol Endocrinol Metab 298: E270 -E277, 2010. First published November 17, 2009 doi:10.1152/ajpendo.00437.2009.-Suboptimal developmental environments program offspring to lifelong metabolic problems. The aim of this study was to determine the impact of protein restriction in pregnancy on maternal liver lipid metabolism at 19 days of gestation (dG) and its effect on fetal brain development. Control (C) and restricted (R) mothers were fed with isocaloric diets containing 20 and 10% of casein. At 19 dG, maternal blood and livers and fetal livers and brains were collected. Serum insulin and leptin levels were determinate in mothers. Maternal and fetal liver lipid and fetal brain lipid quantification were performed. Maternal liver and fetal brain fatty acids were quantified by gas chromatography. In mothers, liver desaturase and elongase mRNAs were measured by RT-PCR. Maternal body and liver weights were similar in both groups. However, fat body composition, including liver lipids, was lower in R mothers. A higher fasting insulin at 19 dG in the R group was observed (C ϭ 0.2 Ϯ 0.04 vs. R ϭ 0.9 Ϯ 0.16 ng/ml, P Ͻ 0.01) and was inversely related to early growth retardation. Serum leptin in R mothers was significantly higher than that observed in C rats (C ϭ 5 Ϯ 0.1 vs. R ϭ 7 Ϯ 0.7 ng/ml, P Ͻ 0.05). In addition, protein restriction significantly reduced gene expression in maternal liver of desaturases and elongases and the concentration of arachidonic (AA) and docosahexanoic (DHA) acids. In fetus from R mothers, a low body weight (C ϭ 3 Ϯ 0.3 vs. R ϭ 2 Ϯ 0.1 g, P Ͻ 0.05), as well as liver and brain lipids, including the content of DHA in the brain, was reduced. This study showed that protein restriction during pregnancy may negatively impact normal fetal brain development by changes in maternal lipid metabolism.programming; development; docosahexaenoic acid; arachidonic acid HUMAN EPIDEMIOLOGICAL (28, 31) and experimental animal studies (16,23,25) have shown that a suboptimal environment either in the womb or early in the neonatal life alters growth and predisposes individuals to lifelong health problems. Maternal dietary deficiencies in pregnancy result in multiple adverse outcomes in the offspring (3, 12). Fetal growth depends mostly on the amount and type of nutrients obtained from the mother. Therefore, the mother must adapt her metabolism to support this continuous draining of substrates. The effects of an altered intrauterine environment can be passed transgenerationally by epigenetic mechanisms involving changes in gene expression (41). During late gestation, maternal liver plays a central role in whole body lipid metabolism. Maternal triglycerides (TG) are not transported intact across the placenta, whereas free fatty acids (FAs), including longchain polyunsaturated fatty acids (LC-PUFAs), can be transported (32). Therefore, a deficient maternal FA intake, particularly essential FAs (...