BACKGROUND: Intrauterine growth restriction (IUGR) followed by postnatal accelerated growth (CG-IUGR) is associated with long-term adverse metabolic consequences, and an involvement of epigenetic dysregulation has been implicated. Peroxisome proliferator activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a key orchestrator in energy homeostasis. We hypothesized that CG-IUGR programed an insulin-resistant phenotype through the alteration in DNA methylation and transcriptional activity of PGC-1 alpha. METHODS: A CG-IUGR rat model was adopted using maternal gestational nutritional restriction followed by infantile overnutrition achieved by reducing the litter size. The DNA methylation was determined by pyrosequencing. The mRNA expression and mitochondrial content were assessed by real-time PCR. The insulin-signaling protein expression was evaluated by western blotting. RESULTS: Compared with controls, the CG-IUGR rats showed an increase in the DNA methylation of specific CpG sites in PGC-1 alpha, and a decrease in the transcriptional activity of PGC-1 alpha, mitochondrial content, protein level of PI3K and phosphorylated-Akt2 in liver and muscle tissues. The methylation of specific CpG sites in PGC-1 alpha was positively correlated with fasting insulin concentration. CONCLUSION: IUGR followed by infantile overnutrition programs an insulin-resistant phenotype, possibly through the alteration in DNA methylation and transcriptional activity of PGC-1 alpha. The genetic and epigenetic modifications of PGC-1 alpha provide a potential mechanism linking early-life nutrition insult to long-term metabolic disease susceptibilities.