title: IUGR with infantile overnutrition programs an insulin-resistant phenotype through DNA methylation of peroxisome proliferator-activated receptor-γ coactivator-1α in rats.
abstract: 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-γ coactivator-1α (PGC-1α) 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-1α.
  
  
  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-1α, and a decrease in the transcriptional activity of PGC-1α, mitochondrial content, protein level of PI3K and phosphorylated-Akt2 in liver and muscle tissues. The methylation of specific CpG sites in PGC-1α was positively correlated with fasting insulin concentration.
  
  
  CONCLUSIONS
  IUGR followed by infantile overnutrition programs an insulin-resistant phenotype, possibly through the alteration in DNA methylation and transcriptional activity of PGC-1α. The genetic and epigenetic modifications of PGC-1α provide a potential mechanism linking early-life nutrition insult to long-term metabolic disease susceptibilities.
authors: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Xuemei
authors: X
authors: Xie
authors: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Tulian
authors: T
authors: Lin
authors: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Meihui
authors: M
authors: Zhang
authors: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Lihong
authors: L
authors: Liao
authors: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Guandou
authors: G
authors: Yuan
authors: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Hongjie
authors: H
authors: Gao
authors: Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Qin
authors: Q
authors: Ning
authors: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Xiaoping
authors: X
authors: Luo
mesh_terms: D053180:Animal Nutrition Sciences; D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005227:Fatty Acids / Q000737:chemistry; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D017422:Sequence Analysis, DNA; D013696:Temperature; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D005227:Fatty Acids; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D014280:Triglycerides; D010100:Oxygen