Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates
| العنوان: | Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates |
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| المؤلفون: | Carrie E. McCurdy, Kenneth N. Maclean, Paul Kievit, Bryan C. Bergman, Rachel C. Janssen, Peter R. Baker, Christopher M. Mulligan, Tyler Dean, Diana L. Takahashi, Travis Nemkov, Kjersti Aagaard, Hua Jiang, Stephanie R. Wesolowski, Angelo D'Alessandro, Jacob E. Friedman |
| المصدر: | Molecular Metabolism, Vol 18, Iss, Pp 25-41 (2018) Molecular Metabolism |
| بيانات النشر: | Elsevier BV, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Steatosis, VIP, variable importance in projection, Hypoxemia, AUC, area under the curve, PC, phosphatidylcholine, 0302 clinical medicine, WSD, Western-style diet, Non-alcoholic Fatty Liver Disease, Pregnancy, Fetal programming, Hyperlipidemia, DAG, diacylglyceride, VLDL, very low-density lipoprotein, Hypoxia, 2. Zero hunger, TG, triglyceride, NEFA, non-esterified fatty acid, NHP, non-human primate, Fatty liver, 3. Good health, Liver, Lipotoxicity, CON, control, OB-WSD, Western-style diet induced obesity group, IV-GTT, intravenous glucose tolerance test, Prenatal Exposure Delayed Effects, Original Article, Female, Diet, Healthy, PLS-DA, partial least squares discriminant analysis, TCA, tricarboxylic acid cycle, NAFLD, non-alcoholic fatty liver disease, lcsh:Internal medicine, medicine.medical_specialty, Offspring, NASH, non-alcoholic steatohepatitis, Citric Acid Cycle, Metabolomic, 030209 endocrinology & metabolism, DNL, de novo lipogenesis, TBARs, thiobarbituric acid reactive substances, OB-DR, diet reversal group, 03 medical and health sciences, Fetus, Internal medicine, medicine, TBARS, Animals, Obesity, AA, amino acid, lcsh:RC31-1245, Molecular Biology, Triglycerides, business.industry, Gluconeogenesis, Maternal Nutritional Physiological Phenomena, Cell Biology, medicine.disease, Oxidative Stress, 030104 developmental biology, Endocrinology, Diet, Western, Macaca, business |
| الوصف: | Objective Non-alcoholic fatty liver disease (NAFLD) risk begins in utero in offspring of obese mothers. A critical unmet need in this field is to understand the pathways and biomarkers underlying fetal hepatic lipotoxicity and whether maternal dietary intervention during pregnancy is an effective countermeasure. Methods We utilized a well-established non-human primate model of chronic, maternal, Western-style diet induced obesity (OB-WSD) compared with mothers on a healthy control diet (CON) or a subset of OB-WSD mothers switched to the CON diet (diet reversal; OB-DR) prior to and for the duration of the next pregnancy. Fetuses were studied in the early 3rd trimester. Results Fetuses from OB-WSD mothers had higher circulating triglycerides (TGs) and lower arterial oxygenation suggesting hypoxemia, compared with fetuses from CON and OB-DR mothers. Hepatic TG content, oxidative stress (TBARs), and de novo lipogenic genes were increased in fetuses from OB-WSD compared with CON mothers. Fetuses from OB-DR mothers had lower lipogenic gene expression and TBARs yet persistently higher TGs. Metabolomic profiling of fetal liver and serum (umbilical artery) revealed distinct separation of CON and OB-WSD groups, and an intermediate phenotype in fetuses from OB-DR mothers. Pathway analysis identified decreased tricarboxylic acid cycle intermediates, increased amino acid (AA) metabolism and byproducts, and increased gluconeogenesis, suggesting an increased reliance on AA metabolism to meet energy needs in the liver of fetuses from OB-WSD mothers. Components in collagen synthesis, including serum protein 5-hydroxylysine and hepatic lysine and proline, were positively correlated with hepatic TGs and TBARs, suggesting early signs of fibrosis in livers from the OB-WSD group. Importantly, hepatic gluconeogenic and arginine related intermediates and serum levels of lactate, pyruvate, several AAs, and nucleotide intermediates were normalized in the OB-DR group. However, hepatic levels of CDP-choline and total ceramide levels remained high in fetuses from OB-DR mothers. Conclusions Our data provide new metabolic evidence that, in addition to fetal hepatic steatosis, maternal WSD creates fetal hypoxemia and increases utilization of AAs for energy production and early activation of gluconeogenic pathways in the fetal liver. When combined with hyperlipidemia and limited antioxidant activity, the fetus suffers from hepatic oxidative stress and altered intracellular metabolism which can be improved with maternal diet intervention. Our data reinforce the concept that multiple “first hits” occur in the fetus prior to development of obesity and demonstrate new biomarkers with potential clinical implications for monitoring NAFLD risk in offspring. Graphical abstract Image 1 Highlights • Maternal WSD increases fetal hypoxemia and utilization of AAs for gluconeogenesis. • Maternal WSD increases fetal oxidative stress and precursors to liver fibrosis. • Carnosine and l-proline uniquely correlated with fetal TG and oxidative stress. • Fetal TGs were correlated with fetal arterial oxygen saturation. • Diet reversal in obese WSD mothers prevents fetal hypoxemia and oxidative stress. |
| تدمد: | 2212-8778 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b06dccd8288a52f01636dbe7fd72ba0fTest https://doi.org/10.1016/j.molmet.2018.09.008Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b06dccd8288a52f01636dbe7fd72ba0f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22128778 |
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