TY - JOUR A1 - Dwi Putra, Sulistyo Emantoko A1 - Reichetzeder, Christoph A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Slowinski, Torsten A1 - Chu, Chang A1 - Krämer, Bernhard K. A1 - Kleuser, Burkhard A1 - Hocher, Berthold T1 - Being born large for gestational age is associated with increased global placental DNA methylation JF - Scientific Reports N2 - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001). KW - fetal origins hypothesis KW - birth weight KW - repetitive elements KW - glucocorticoid receptor KW - nutrient transport KW - growth restriction KW - later health KW - pregnancy KW - genes KW - patterns Y1 - 2020 U6 - https://doi.org/10.1038/s41598-020-57725-0 SN - 2045-2322 VL - 10 IS - 1 SP - 1 EP - 10 PB - Springer Nature CY - London ER - TY - JOUR A1 - Bär, Ludmilla A1 - Feger, Martina A1 - Fajol, Abul A1 - Klotz, Lars-Oliver A1 - Zeng, Shufei A1 - Lang, Florian A1 - Hocher, Berthold A1 - Föller, Michael T1 - Insulin suppresses the production of fibroblast growth factor 23 (FGF23) JF - Proceedings of the National Academy of Sciences of the United States of America N2 - Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans. KW - PI3K KW - PKB/Akt KW - Klotho KW - phosphate Y1 - 2018 U6 - https://doi.org/10.1073/pnas.1800160115 SN - 0027-8424 VL - 115 IS - 22 SP - 5804 EP - 5809 PB - National Acad. of Sciences CY - Washington ER - TY - JOUR A1 - Tao, Ting A1 - Su, Qiongli A1 - Xu, Simeng A1 - Deng, Jun A1 - Zhou, Sichun A1 - Zhuang, Yu A1 - Huang, Yanjun A1 - He, Caimei A1 - He, Shanping A1 - Peng, Mei A1 - Hocher, Berthold A1 - Yang, Xiaoping T1 - Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis JF - Journal of cellular physiology N2 - Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer. KW - bladder cancer cells KW - FASN KW - p-AKT KW - PKM2 KW - p-mTOR KW - SREBP-1c Y1 - 2018 U6 - https://doi.org/10.1002/jcp.27129 SN - 0021-9541 SN - 1097-4652 VL - 234 IS - 3 SP - 3088 EP - 3104 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Li, Jian A1 - Tsuprykov, Oleg A1 - Yang, Xiaoping A1 - Hocher, Berthold T1 - Paternal programming of offspring cardiometabolic diseases in later life JF - Journal of hypertension KW - cardiometabolic diseases KW - epigenetics KW - offspring KW - paternal programming KW - spermatogenesis KW - transgenerational effects Y1 - 2016 U6 - https://doi.org/10.1097/HJH.0000000000001051 SN - 0263-6352 SN - 1473-5598 VL - 34 SP - 2111 EP - 2126 PB - Wiley-Blackwell CY - Philadelphia ER -