Location: Arkansas Children's Nutrition CenterTitle: Offspring insulin and adiponectin signaling are targets of in utero programming following exposure to maternal overweight during gestation) Author
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 7/1/2009
Publication Date: N/A
Citation: Interpretive Summary: Maternal body composition at conception has long-term consequences for the health of the offspring. We have studied whether in utero exposure to maternal obesity increases the risk of obesity in the offspring in later-life using a model of obesity in the rat. Using this model we have demonstrated that maternal obesity via metabolic factors independent of genetic influences leads to increased risk of obesity in the offspring when challenged with a high fat diet. In the present studies we investigated changes in expression of genes in the liver of offspring at weaning prior to development of obesity. Using microarrays we identified expression of 147 transcripts to be altered in the offspring of overweight dams. Of these, genes involved in production of fat regulated via the factor SREBP-1 were significantly up-regulated. In addition, the serum levels of the hormones adiponectin and FGF21 were down-regulated. Since, these hormones are involved in increasing insulin sensitivity and energy expenditure, our findings suggest that maternal obesity may program the responsiveness in the offspring of overweight dams and hence may increase susceptibility to weight gain and obesity.
Technical Abstract: The risk of obesity in adult-life is subject to programming during gestation. To examine whether in utero exposure to maternal overweight (OW) increases the risk of obesity in the offspring, we developed an overfeeding-based model of maternal OW in rats utilizing intragastric feeding of diets via total enteral nutrition (TEN). Female rats overfed 15% excess calories/d via TEN for 3 wks prior to conception developed excessive body-weight gain, adiposity, serum insulin, leptin and insulin resistance. Exposure to maternal OW was limited in utero by cross-fostering pups at birth. While numbers of pups, size, and body weights at birth and weaning were not affected by maternal OW, male offspring from OW dams gained remarkably greater (p < 0.005) body weight and higher %body fat assessed by NMR, X-ray computerized tomography, and weights of adipose tissues when fed high fat diet (45% fat calories). Microarray analyses of offspring livers at postnatal day 21 revealed 147 transcripts were significantly (+/-1.8-fold, p < 0.05) altered by maternal OW. Of these, expression of 20 transcripts known to be regulated by SREBP-1 was significantly increased. Expression of SREBP-1 mRNA and 10 other transcripts identified via microarray analyses was confirmed using real-time RT-PCR. Nuclear levels of SREBP-1 and recruitment to promoter binding sites on the FASN promoter were confirmed via TransAM ELISA and chromatin immunoprecipitation analyses, respectively. In addition, microarray analyses and real-time RT-PCR revealed decreased expression of 10 PPAR-a regulated genes, including FGF21. FGF21 serum levels were confirmed to be lower using RIA (p< 0.05) in OW dam offspring. Further, serum levels of total adiponectin (p = 0.07) and HMW adiponectin (p < 0.05) were lower in OW dam offspring at weaning. No changes in %fat mass or adiponectin mRNA expression in the adipose tissue was observed. However, hepatic expression of AdipoR1 and R2 were lower in OW dam offspring. Finally, phosphorylation of the adiponectin target in the liver, AMPK (at Thr172) was significantly decreased in livers of OW dam offspring. Our data suggest that maternal OW at conception leads to increased lipogenic gene expression in concert with decreased adiponectin-AMPK signaling in the liver of young offspring. These mechanisms may be critical in determining the increased predisposition of offspring to obesity.