Research Article Details
| Article ID: | A52552 |
| PMID: | 25675425 |
| Source: | Pediatr Res |
| 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. CONCLUSION: 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. |
| DOI: | 10.1038/pr.2015.32 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T05 | Peroxisome proliferator-activated receptor gamma | PPARG | agonist | Nuclear hormone receptor | P37231 | PPARG_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D581 | sobetirome | Chemical drug | -- | Thyroid hormone receptor beta agonists | Enhance lipid metabolism | Under investigation | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |