arXiv:1906.05572v1 [cs.CL]

Non-technical summary An excess production of liver glucose is common in patients with diabetes, and animal studies show that female rats who consume a high-fat diet during pregnancy may give birth to offspring who are more likely to develop diabetes in adulthood. However, how this may be occurring remains poorly understood. The present study investigated the effect of a maternal high fat diet on fetal genes in the liver that control the production of glucose, and the potential regulatory mechanisms of these genes. We observed that pups of high fat-fed dams were heavier and had higher blood glucose at the time of delivery than pups of dams fed the control diet. While the high fat-fed dams themselves did not have increased blood glucose, their pups had higher expression of genes to make glucose in addition to elevated blood glucose. Our study demonstrates that exposure to a high fat diet during pregnancy programs the over-production of glucose in livers of offspring, which has the potential to lead to type II diabetes in childhood and adulthood.Abstract In insulin resistance and type II diabetes, there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycaemia. Studies in experimental animals have provided evidence that consumption of high fat (HF) diets by female rats programs the progeny for glucose intolerance in adulthood, but the mechanisms behind the in utero programming remain poorly understood. The present study analysed the effect of a maternal HF diet on fetal gluconeogenic gene expression and potential regulation mechanism related to histone modifications. Dams were fed either a Control (C, 16% kcal fat) or a high-fat (HF, 45% kcal fat) diet throughout gestation. Livers of the offspring were collected on gestational day 21 and analysed to determine the consequences of a maternal HF diet on molecular markers of fetal liver gluconeogenesis. We demonstrated that offspring of HF-fed dams were significantly heavier and had significantly higher blood glucose levels at the time of delivery than offspring of dams fed the C diet. While maternal gluconeogenesis and plasma glucose were not affected by the HF diet, offspring of HF-fed dams had significantly higher mRNA contents of gluconeogenic genes in addition to the elevated plasma glucose. In addition to increased transcription rate, a gestational HF diet resulted in modifications of the Pck1 histone code in livers of offspring. Our results demonstrate that in utero exposure to HF diet has the potential to program the gluconeogenic capacity of offspring through epigenetic modifications, which could potentially lead to excessive glucose production and altered insulin sensitivity in adulthood.

Overnutrition, such as a high-fat (HF) diet, is a feature followed by some in developed nations that leads to obesity and fatty liver disease. In rats, when fed a fat-high diet, some develop obesity (obesity prone, OP) while others display an obesity-resistant (OR) phenotype. The present study investigated the differences between OP and OR rats on their activation of hepatic cellular senescence pathways on a HF diet. Male OP and OR rats were fed a HF diet containing 45% kcal from fat for 13 wk, and livers were collected for analysis by quantitative real-time PCR, Western blot, and chromatin immunoprecipitation. OP rats were 41% heavier than OR rats, despite consuming the same amount of food. Triacylglycerol levels were increased significantly in both plasma and liver of OP rats. Gene analysis demonstrated a significant increase of both the amount and the transcription rates of p16(INK4a) and p21(Cip1) mRNA in OP rats. The increased p16(INK4a) and p21(Cip1) also caused a significant decrease in the level of phosphorylation of retinoblastoma protein. In OP rats, the increase of p16(INK4a) was associated with the higher acetylation levels of histone H4 at the p16(INK4a) promoter and coding region and lower methylation level of histone H3 lysine-27 in the p16(INK4a) coding region. The increase of p21(Cip1) was associated with increased acetylation of both histone H3 and H4 and decreased trimethylation of histone H3 lysine-27 at the p21(Cip1) promoter. In the p21(Cip1) coding region, dimethylation of histone H3 lysine-4 was significantly higher (P <0.05) in livers of OP rats compared with OR rats.

Purpose Whether it is safe for estrogen receptor positive (ER+) breast cancer patients to consume soy isoflavone genistein (GEN) remains controversial. We compared the effects of GEN intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen (TAM) therapy using a preclinical model. Experimental Design Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm GEN from postnatal day 15 onwards (lifetime GEN). Mammary tumors were induced with 7,12-dimethylbenz(a)anthracene (DMBA), after which a group of control diet fed rats were switched to GEN diet (adult GEN). When the first tumor in a rat reached 1.4 cm in diameter, TAM was added to the diet, and a subset of previously only control diet fed rats also started GEN intake (post-diagnosis GEN). Results Lifetime GEN intake reduced de novo resistance to TAM, compared with post-diagnosis GEN groups. Risk of recurrence was lower both in the lifetime and adult GEN groups than in the post-diagnosis GEN group. We observed downregulation of unfolded protein response (UPR) and autophagy related genes (GRP78, IRE1α, ATF4 and Beclin-1), and genes linked to immunosuppression (TGFβ and Foxp3), and upregulation of cytotoxic T cell marker CD8a in the tumors of the lifetime GEN group, compared with controls, post-diagnosis, and/or adult GEN groups. Conclusions GEN intake mimicking Asian consumption patterns improved response of mammary tumors to TAM therapy, and this effect was linked to reduced activity of UPR and pro-survival autophagy signaling, and increased anti-tumor immunity.

to further understand the molecular pathogenesis of desmoplastic small round cell tumor (DSRct), a fatal malignancy occurring primarily in adolescent/young adult males, we used next-generation RNA sequencing to investigate the gene expression profiles intrinsic to this disease. RNA from DSRCT specimens obtained from the Children's Oncology Group was sequenced using the Illumina HiSeq 2000 system and subjected to bioinformatic analyses. Validation and functional studies included WT1 ChIP-seq, EWS-WT1 knockdown using JN-DSRCT-1 cells and immunohistochemistry. A panel of immune signature genes was also evaluated to identify possible immune therapeutic targets. Twelve of 14 tumor samples demonstrated presence of the diagnostic EWSR1-WT1 translocation and these 12 samples were used for the remainder of the analysis. RNA sequencing confirmed the lack of fulllength WT1 in all fusion positive samples as well as the JN-DSRCT-1 cell line. ChIP-seq for WT1 showed significant overlap with genes found to be highly expressed, including IGF2 and FGFR4, which were both highly expressed and targets of the EWS-WT1 fusion protein. In addition, we identified CD200 and CD276 as potentially targetable immune checkpoints whose expression is independent of the EWS-WT1 fusion gene in cultured DSCRT cells. In conclusion, we identified IGF2, FGFR4, CD200, and CD276 as potential therapeutic targets with clinical relevance for patients with DSRct. DSRCT was first described by Gerald and Rosai 1 as a highly malignant soft-tissue sarcoma occurring in adolescent and young adults, especially in males. It often presents with widespread disease with malignant foci present throughout the peritoneal cavity. Despite intense multi-agent chemotherapy, surgery, radiation therapy, and incorporation of other treatment modalities like high-dose chemotherapy with autologous stem cell rescue, 5-year event-free survival remains dismal at less than 20%, while the median survival time is approximately 2.5 years 2. Novel therapies are therefore urgently needed to improve the outcomes for patients with this disease.