Maternal protein restriction in rats leads to reduced PGC-1α expression via altered DNA methylation in skeletal muscle

Abstract

Intrauterine growth retardation (IUGR) is thought to program insulin resistance, type 2 diabetes and other metabolic diseases in later life. Skeletal muscle is an important tissue involved in regulating the metabolism. We therefore hypothesized that the regulation of glucose- and lipid-related genes in skeletal muscle may contribute to metabolic changes in rats with IUGR. In this study, IUGR rats were bred from pregnant rats fed a protein-restricted (PR) diet. Insulin resistance (IR)-related metabolic parameters and the expression of key regulatory IR genes such as peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and glucose transporter 4 (GLUT4) were measured in skeletal muscle from 18-month-old female IUGR rats. The methylation status of promoters of PGC-1α and GLUT4 were assessed in the same tissues. During the aging process, IUGR rats exhibited catch-up growth and obesity. In old age, they showed impaired glucose tolerance demonstrated by high glucose and insulin AUC (area under the curve) values. The expression of glucose transporter 4 (GLUT4) and PGC-1α in skeletal muscle was significantly reduced in IUGR rats. Mean CpG island methylation in the PGC-1α promoter sequence was significantly increased. These results suggest that a PR diet during gestation may induce epigenetic changes, such as DNA methylation, in the promoters of specific genes. The changes may affect gene expression and account for the metabolic alterations in female rats with IUGR.

Metabolic response to 36 hours of fasting in young men born small vs appropriate for gestational age

“…PPARGC1A is thought to play a key role in the control of mitochondrion content and function, as well as in the control of energy metabolism and insulin action [18,38]. To the best of our knowledge, increased PPARGC1A methylation represents the most consistent epigenetic alteration in the skeletal muscle of SGA individuals [39]. Transcriptional repression of PPARGC1A among SGA individuals during fasting could therefore theoretically explain the decreased mitochondrial EE in SGA participants during fasting.…”

Nutritional epigenetics with a focus on amino acids: implications for the development and treatment of metabolic syndrome

“…Other studies have focused on the lack of dietary protein intake on fetal programming in rodents. In rats, a protein restricted diet during pregnancy can induce CpG island methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the skeletal muscles of female IUGR offspring [28]. Interestingly, these subjects have insulin resistance in association with the downregulation of PGC-1α and GLUT4 expression in skeletal muscles [28].…”

IUGR with infantile overnutrition programs an insulin-resistant phenotype through DNA methylation of peroxisome proliferator–activated receptor-γ coactivator-1α in rats

“…Recently, the DNA methylation level of PGC-1α promoter in umbilical cord has been found to positively correlate with maternal pregestational BMI (24); moreover, the PGC-1α methylation level is increased in the muscle of low-birth-weight adults (19,25), and 5-d overfeeding may influence the DNA methylation of PGC-1α in a birth-weight-dependent manner (19); besides, maternal methyl donor-deficient diet leads to PGC-1α protein hypomethylation in the liver of the pups with subsequent impairment of fatty acid oxidation (26), suggesting that both Articles prenatal and postnatal nutritional status may play a crucial role in metabolic programing through the epigenetic modification of PGC-1α. In our study, the methylation level of CpG sites -787 and -803 of PGC-1α promoter was higher in the liver and muscle of CG-IUGR rats while the methylation level of other CpG sites was comparable between the groups, and the methylation level of specific CpG sites was positively correlated with fasting insulin level.…”