Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat

The nutritional environment encountered during fetal life is strongly implicated as a determinant of lifelong metabolic capacity and risk of disease. Pregnant rats were fed a control or low- protein ( LP) diet, targeted to early ( LPE), mid-( LPM), or late ( LPL) pregnancy, or throughout gestation ( LPA). The offspring were studied at 1, 9, and 18 mo of age. All LP- exposed groups had similar plasma triglyceride, cholesterol, glucose, and insulin concentrations to those of controls at 1 and 9 mo of age, but by 18 mo there was evidence of LP- programmed hypertri-glyceridemia and insulin resistance. All LP- exposed groups exhibited histological evidence of hepatic steatosis and were found to have two-to threefold more hepatic triglyceride than control animals. These phenotypic changes were accompanied by age- related changes in mRNA and protein expression of the transcription factors SREBP-1c, ChREBP, PPAR gamma, and PPAR alpha and their respective downstream target genes ACC1, FAS, L- PK, and MCAD. At 9 mo of age, the LP groups exhibited suppression of the SREBP-1c-related lipogenic pathway but between 9 and 18 mo underwent a switch to increased lipogenic capacity with a lower expression of PPAR gamma and MCAD, consistent with reduced lipid oxidation. The findings indicate that prenatal protein restriction programs development of a metabolic syndrome- like phenotype that develops only with senescence. The data implicate altered expression of SREBP- 1c and ChREBP as key mediators of the programmed phenotype, but the basis of the switch in metabolic status that occurred between 9 and 18 mo of age is, as yet, unidentified.