Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High consumption of fructose-sweetened beverages has been linked to a high prevalence of chronic metabolic diseases. We have previously shown that a short course of fructose supplementation as a liquid solution induces glucose intolerance in female rats. In the present work, we characterized the fructose-driven changes in the liver and the molecular pathways involved. To this end, female rats were supplemented or not with liquid fructose (10%, w/v) for 7 or 14 days. Glucose and pyruvate tolerance tests were performed, and the expression of genes related to insulin signaling, gluconeogenesis and nutrient sensing pathways was evaluated. Fructose-supplemented rats showed increased plasma glucose excursions in glucose and pyruvate tolerance tests and reduced hepatic expression of several genes related to insulin signaling, including insulin receptor substrate 2 (IRS-2). However, the expression of key gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was reduced. These effects were caused by an inactivation of hepatic forkhead box O1 (FoxO1) due to an increase in its acetylation state driven by a reduced expression and activity of sirtuin 1 (SIRT1). Further contributing to FoxO1 inactivation, fructose consumption elevated liver expression of the spliced form of X-box-binding-protein-1 as a consequence of an increase in the activity of the mammalian target of rapamycin 1 and protein 38-mitogen activated protein kinase (p38-MAPK). Liquid fructose affects both insulin signaling (IRS-2 and FoxO1) and nutrient sensing pathways (p38-MAPK, mTOR and SIRT1), thus disrupting hepatic insulin signaling without increasing the expression of key gluconeogenic enzymes.
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PMID:Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats. 2444 51

Litter size and birth weights are limited by uterine capacity, defined as the ability of the uterus to maintain the appropriate development of some number of conceptuses. Uterine capacity is the result of the combined effects of uterine, placental and embryo/fetal function. The number of living conceptuses that the uterus is capable of supporting is greater during early gestation compared to later gestation. Plots of log fetal weight versus log placental weight also indicate that fetal weights are less sensitive to reduced placental weight (and therefore reduced intrauterine space) in early gestation compared to late gestation. However, even in late gestation, mechanisms still exist that maintain fetal growth when the size of the placenta is reduced. One such mechanism is likely to be improved development of the folded placental-epithelial/maternal-epithelial bilayer. Fold depth, and therefore the maternal fetal interactive surface, increases as gestation advances and is greater in placenta from small fetuses. On the fetal side of the placenta, the epithelial bilayer is embedded in stromal tissue. Glycosaminoglycans are major components of stroma, including hyaluronan and heparan sulfate. Hyaluronidases and heparanases are present within placental tissues, and likely play roles in modification of stromal components to facilitate fold development. Glycosaminoglycans are polymers of forms of glucose (glucosamine, glucuronic acid, iduronic acid) suggesting that glycosaminoglycan synthesis may compete with the glucose needs of the developing fetus. Pig conceptuses are fructogenic, such that a substantial portion of glucose transferred from mother to fetus is converted to fructose. Fructose is an intermediate product in the synthesis of glucosamine from glucose, and glucosamine is linked to regulation of trophoblast cell proliferation through regulation of mTOR. These findings suggest a link between glucose, fructose, glucosamine synthesis, GAG production, and placental morphogenesis, but the details of these interactions remain unclear. In addition, recent placental epithelial transcriptome analysis identified several glucose, amino acid, lipid, vitamin, mineral and hormone transporter mechanisms within the placenta. Further elucidation of mechanisms of placental morphogenesis and solute transport could provide clues to improving nutrient transport to the pig fetus, potentially increasing litter size and piglet birth weights.
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PMID:Placental accommodations for transport and metabolism during intra-uterine crowding in pigs. 2593 25

The Pyruvate kinase isozymes M2 (PKM2) protein is a metabolic enzyme that regulates the final step of glycolysis. This enzyme is present in highly proliferating cells and is expressed in the placenta. We recently demonstrated upregulated placental PKM2 during human intrauterine growth restriction (IUGR). Our current objective was to determine PKM2 regulation of trophoblast invasion, trophoblast PKM2 localization as well as mTOR protein expression, and to determine effects of activation of PKM2 during IUGR. Human placental tissues were obtained and analyzed by immunohistochemistry and western blot. Trophoblast cells were cultured in normoxic and hypoxic conditions and real time cell invasion and PKM2 protein were determined during activation (Fructose-6-bisphosphate; FBP6) or inhibition (Shikonin) of PKM2. In vivo studies determined the effects of PKM2 activation on placental and fetal weights. IUGR samples had elevated levels of p-PKM2. Different trophoblast PKM2 localization and expression was observed during normoxia and hypoxia. Decreased trophoblast invasion and PKM2 expression was observed during mTOR inhibition. Protection from decreased placental and fetal weights was observed by PKM2 activation. We conclude that PKM2 regulates trophoblast cell invasion depending on its subcellular location. Our results suggest that PKM2 regulation in trophoblast cells is more directly affected during hypoxia and its expression is regulated by mTOR activity. Additionally, we conclude that activation of PKM2 could reverse and/or rescue the deceased placental and fetal weights observed during IUGR. These results suggest that PKM2 could be a mediator of trophoblast cell invasion and its abundance influences the development of complicated pregnancies like IUGR.
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PMID:Regulation of trophoblast cell invasion by Pyruvate Kinase isozyme M2 (PKM2). 3307 34