Project description:We previously reported that a low versus high glycemic index (GI) diet on a high fat (30% kcal fat) background (LGI and HGI, respectively) significantly retarded adverse health effects in C57BL/6J male mice. The LGI diet enhanced whole body insulin sensitivity and repressed high fat diet-induced body and adipose tissue weight gain, resulting in reduced serum leptin and resistin levels (Faseb J 2009; 23: 1092-1101). How white adipose tissue (WAT) is effected is examined in the present study. We characterized the molecular mechanisms underlying the GI-mediated effects in WAT using whole genome transcriptomics technology. We show that a LGI vs. HGI diet mainly exerts its beneficial effects on substrate metabolism, especially insulin signaling of fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression in line with lower WAT mass, but it might also be due to altered insulin sensitivity. An important transcription factor showing enhanced expression is PPARgamma. Furthermore, serum levels of triglycerides, total cholesterol, HDL- and LDL-cholesterol were significantly reduced by a LGI vs. HGI diet, and muscle insulin sensitivity was significantly increased as analyzed by PKB/Akt phosphorylation. Cumulatively, even though these mice were fed a high fat diet, the low versus high GI induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones (TZDs) to treat insulin resistance and statins and plantsterols/stanols for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans. We analyzed 19 epididymal whie adipose tissue (epiWAT) samples from a 13 week High fat diet, Low glycemic index dietary group (LGI, n=9) versus a High fat diet, High glycemic index dietary group (HGI, n=10) after 13 weeks of feeding wildtype C57BL/6J male adult mice. Of the 19 arrays, we excluded 2 arrays for downstream analysis based on quality control (total final set contains 8 LGI and 9 HGI samples).

Project description:Background: Consumption of high fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in mouse offspring fed a high fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Results: Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Conclusions: Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets during gestation and lactation can alter global DNA methylation in liver. This may be one mechanism by which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health. Female wild type C57BL/6 mice (Animal Resource Centre, Western Australia) were fed a High Fat diet containing low levels of selenium and folate (HF-Low) for 7 days prior to mating with male C57BL/6 mice (Ruakura Small Animal Facility, Hamilton, New Zealand). Mothers were maintained on the HF-Low diet throughout gestation and lactation. Offspring of these female mice were randomly assigned to one of two different dietary treatments: either the same diet as the mothers (HF-Low), or a High Fat diet containing adequate selenium and folate (HF-Suf). At 12 weeks of age, mice were euthanized and colon and liver samples taken for microarray, proteomics, and DNA methylation analyses. Genomic DNA, total RNA and protein from whole colon and liver tissue was extracted using an AllPrepM-BM-. DNA/RNA/Protein mini kit (Qiagen, Cat number 80004). Colon and liver RNA from six female offspring on the HF-Low diet was compared with colon and liver RNA from six female offspring on the HF-Suf diet. All individual RNA samples were hybridized against a common reference RNA on separate arrays. The reference RNA was prepared by pooling in equimolar proportions RNA extracted from the intestine and liver of twelve female C57BL/6 mice, these being all of the mice from which samples were derived for microarray analysis in the current study.

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