Adaptive responses by mouse fetus to a maternal HLE diet by downregulating SREBP1: a microarray- and bio-analytic-based study

Abstract

health problems as the ones observed in epidemiological studies ( 4,5 ). So, maternal high-fat diet is an important predisposing factor to the onset and development of obesity, insulin resistance, and cardiovascular diseases in offspring ( 6 ). Indeed, a high-fat diet during gestation has been shown to lead to a lack of increase in insulin release and ATP content in response to glucose stimulation in islets from 3-month-old male and female offspring ( 5 ).However, the mechanisms linking high-fat nutrition in early life with later health problems remain unclear. Preliminary work has been performed on several candidate mechanisms, including: 1 ) white adipose tissue glucocorticoid sensitivity ( 7 ); 2 ) gene modifi cation status, such as DNA methylation (epigenetic mechanism) ( 4 ); 3 ) oxidative stress in dams, which might be transferred to the pups during gestation, later promoting disease development in the offspring ( 8 ); and 4 ) a maternal high-fat diet by itself, which triggers lipotoxicity in the fetal livers and later affects the offspring's health status ( 9 ). Indeed, the metabolic alterations usually observed during pregnancy combined with increased dietary fat intake, increase the triglycerides available to be hydrolyzed for transfer to the offspring, inducing an adaptive toxic response in the offspring's liver; this lipotoxicity leads to macrophage infi ltration into the liver, and to increased cytokine secretion. This infl ammatory state activates the pathways involved in oxidative stress and in gluconeogenesis ( 9 ). These conditions may predispose the offspring to alterations in their lipid metabolism in adult life.An understanding of how maternal nutrients infl uence offspring's development of adult diseases may be gained using proteomic methodologies and microarray analyses.Abstract Maternal diet has long been recognized as a signifi cant factor affecting offspring development and health, but the target genes affected by a maternal high-lipid diet are currently unknown. In this study, the gene expression profi le of neonatal mouse liver was analyzed using gene chips to identify genes with signifi cant up-or downregulated expression levels due to maternal high-fat diet during gestation. Real-time PCR and Western blotting were used to measure key genes selected using microarray. Serum lipid, glucose, and insulin levels in adult offspring from dams fed with chow or a high-lipid diet were measured using commercial kits. Results indicate that the expression of genes involved in cholesterol and fatty acid synthesis were signifi cantly inhibited, while the expression of genes involved in glycolysis were signifi cantly decreased by maternal high-lipid diet during gestation. SREBP1 might be the key gene regulating genes involved in fatty acid, glucose, and cholesterol metabolism in response to a maternal high-fat diet. Maternal nutrient intake during gestation has long been recognized as a signifi cant factor affecting the incidence of features of the adult metabolic syndrome in offspring. Indeed, human ...

Icariin Is A PPARα Activator Inducing Lipid Metabolic Gene Expression in Mice

“…Srebp1 is a key transcription factor and Fasn is the key enzyme of lipogenesis [30,43]. The expression of the Elovl3 is under the control of PPARα [44].…”

Association of Maternal Prepregnancy Weight with Offspring Adiposity Throughout Adulthood over 37 Years of Follow‐up

“…The association between maternal prepregnancy overweight and obesity and offspring BMI, which persists after adjustment for genetic and lifestyle factors, supports previous research describing intergenerational inheritance of metabolic outcomes beyond the inheritance of genetic sequence variants and learned behavior. Although the mechanism underlying fetal programming of obesity is not fully understood, both animal and human models examining the fetal overnutrition hypothesis have supported a possible epigenetic link between maternal and offspring adiposity . Numerous genomic regulatory mechanisms have been implicated in the intergenerational epigenetic inheritance of metabolic disease, including nuclear and ribosomal DNA methylation, histone modifications, and noncoding microRNAs.…”

“…Numerous genomic regulatory mechanisms have been implicated in the intergenerational epigenetic inheritance of metabolic disease, including nuclear and ribosomal DNA methylation, histone modifications, and noncoding microRNAs. In murine models, maternal obesity has been associated with differential methylation of genes involved in fatty acid, cholesterol, and glycogen metabolism . In mammalian fetal models, microRNAs previously linked to CVD and insulin signaling have been differentially expressed among animals exposed to maternal obesity compared with mothers with normal weight .…”

“…In murine models, maternal obesity is associated with differential methylation of genes involved in fatty acid, cholesterol, and glycogen metabolism. 33,34 In mammalian fetal models, miRNAs previously linked to CVD and insulin signaling are differentially expressed among animals exposed to maternal obesity compared to normal weight mothers. 36,37 Human studies have demonstrated associations between maternal BMI and offspring methylation levels.…”

Gene expression and DNA methylation as mechanisms of disturbed metabolism in offspring after exposure to a prenatal HF diet

“…The observed downregulation of SREBP signaling is in agreement with two previous studies that examined the effect of a maternal HF diet on offspring livers. These studies reported that SREBP gene and protein expression were diminished and that this regulated the observed decrease in mRNA expression of genes involved in fatty acid, cholesterol, and steroid biosynthesis, and other SREBP-related functions (45, 46). In contrast, two other studies found an increase in mRNA expression of Srebp1c and some of its downstream genes involved in de novo lipogenesis in response to a prenatal HF diet (13, 14).…”