Progress 07/01/08 to 06/30/11
Outputs
OUTPUTS: To test the effect of maternal nutrient deficiency on placental function, multiparous ewes received 100% (control, C, n = 13) or 50% (nutrient restricted, NR, n = 14) of NRC dietary requirements from 28-78 days of gestation (dG). On d78, 5 C and 6 NR ewes were necropsied. The remaining 8 C and 8 NR ewes were fed to 100% of NRC from d78-d135 and necropsied. Cotyledonary (COT) tissue was evaluated for protein and mRNA expression [fatty acid transporter (FATP)1, FATP4, CD36, glucose transporter (GLUT)1 and GLUT3], mRNA expression only [placenta fatty acid binding protein (FABPpm) and lipoprotein lipase (LPL)], or expression of phosphorylated and total protein forms of AMP-activated protein kinase (AMPK) α, acetyl-CoA carboxylase (ACC), extracellular signal-regulated kinase (Erk)1/2, mammalian target of rapamycin (mTOR) and protein kinase B (Akt)]. On d78, but not d135, placental and fetal weights were reduced (P < 0.05) in NR vs. C ewes. Maternal circulating glucose, insulin and leptin levels were decreased in NR vs. C ewes on d78 (P < 0.05) but similar at d135. Fetal blood glucose and triglyceride levels were lower in NR vs. C ewes (P < 0.05) on d78, but similar on d135. On d78, GLUT1, FATP4, CD36 mRNA and protein expression levels, FABPpm mRNA level, and leptin protein level were all increased (P < 0.05) in COT of NR vs. C ewes. AMPK, ACC, and Erk1/2 activities were also increased (P < 0.05) in NR vs. C COT on d78. In contrast, only FATP4 was increased (P < 0.05) at both the mRNA and protein levels in COT of NR realimented vs. C ewes on d135. These data demonstrate placental adaptation to maternal NR through increasing nutrient transporter production and growth signaling activity. In addition, nonpregnant ewes were randomly assigned to a control group [100% of National Research Council (NRC) recommendations] or over-nourished group (OB, 150% of NRC) from 60 days before conception to 75 or 135 dG, when placental cotyledonary tissue was collected for analysis. Fetuses of OB ewes were markedly heavier (P < 0.05) on 75 dG than fetuses from control ewes, but this difference disappeared by 135 dG. Maternal obesity markedly increased (P < 0.05) cholesterol and triglyceride concentrations of both maternal and fetal blood. There is no difference in lipoprotein lipase mRNA expression between control and OB group at either gestational age. On 75 dG, the mRNA expression of FATP1 (P < 0.05), FATP4 (P = 0.08), and fatty acid translocase CD (cluster of differentiation) 36 (P < 0.05) proteins were more enhanced in cotyledonary tissue from OB than control ewes; consistently, protein expression of FATP1 and FATP4 was increased (P < 0.05). Similarly, on 135 dG, the mRNA levels of FATP1, FATP4, and CD36 were all higher (P < 0.05), but only FATP4 protein content was enhanced (P < 0.05) in OB cotyledonary tissue. Peroxisome proliferator-activated receptor (PPAR)-γ regulates the expression of FATPs. Both the mRNA expression and protein content of PPARγ were increased in OB cotyledonary in the mid-gestation. In summery, our data showed that maternal nutrition affects nutrient transportation across placenta, and AMPK likely plays an important role. PARTICIPANTS: Meijun Zhu, PD devotes 20% effort to this project. Adam Uthlaut, Research Scientist; 10% Collaborator: Stephen P. Ford, Professor, 5% Training or professional development: Yan Ma, Ph.D. student, 50%; Hui Wang, Ph.D. student, 30%. TARGET AUDIENCES: Scientific community PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Placenta mediates nutrient delivery from maternal to fetal circulation, and nutrient availability directly impacts fetal growth and development. Recent studies show that proper fetal development is crucial for the growth performance of offspring. Our data indicated that AMPK has regulatory roles in the placental functions. Knowledge obtained from our studies will likely provide molecular targets to improve cross-placental nutrient delivery and ensure proper fetal development, improving growth performance of progeny.
Publications
- Ma, Y., M. J. Zhu, A. B. Uthlaut, M. J. Nijland, P. W. Nathanielsz, B. W. Hess, and S. P. Ford. (2011). Up-regulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes. Placenta. 32: 255-263.
- Zhu, M. J., Y. Ma, N. M. Long, and S. P. Ford. (2010). Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299: R1224-R1231.
- Zhu, M. J., M. Du, P. W. Nathanielsz, and S. P. Ford. (2010). Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokines expression in the mid-gestation sheep placenta. Placenta. 31: 387-391.
- Zhu, M. J., M. Du, M. J. Nijland, P. W. Nathanielsz, B.W. Hess, G. E. Moss, S. P. Ford. (2009). Down-regulation of growth signaling pathways linked to a reduced cotyledonary vascularity in placentomes of overnourished, obese pregnant ewes. Placenta 30: 405-410.
- Ma. Y., M. J. Zhu, L. Zhang, S. M. Hein, P. W. Nathanielsz, and S. P. Ford. (2010). Maternal obesity and overnurtrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299: R249-R258.
- Yan, X., Y. Huang, H. Wang, M. Du, B.W. Hess, S. P. Ford, P.W. Nathanielsz, and M. J. Zhu. (2011). Maternal obesity induces sustained inflammation in both fetal and offspring large intestine of sheep. Inflammatory Bowel Diseases, 17:1513-1522.
- Wang, H., J. Zhao, Y. Huang, X. Yan, A.M. Meyer, M. Du, K. Vonnahme, L. Reynolds, J. Caton and M. J. Zhu. (2012). Effects of maternal plane of nutrition and elevated dietary selenium in first parity ewe on inflammatory response in the ovine neonatal gut. Journal of Animal Science, 90: 325-333.
- Zhu, M. J., M. Du, P. W. Nathanielsz, and S. P. Ford. (2009). Maternal obesity (MO) induced inflammatory response in ewe placentomes at 75 days gestation (dG). Abstract # 341. Society for Gynecologic Investigation, 2009 annual meeting, Glasgow, Scotland, March 17-21.
- Wang, H., J. Zhao, Y. Huang, X. Yan, A. M. Meyer, M. Du, K. Vonnahme, L. Reynolds, J. Caton and M. J. Zhu. (2010). Excessive maternal selenium intake induces inflammatory response in the ovine fetal gut. 2010 ADSA-CSAS-ASAS Joint Annual Meeting, Denver, CO, July 11-15
- Zhu, M. J., M. Du, C. Tong, B.W. Bret, S. P. Ford and P. W. Nathanielsz. (2009). Maternal over-nutrition and obesity induced inflammatory response in the fetal ileum of sheep Society for the Study of Reproduction 42nd annual meeting, Pittsburgh, Pennsylvania, July 18-22.
- Yan, X., M. Du, B.W. Bret, S. P. Ford, P. W. Nathanielsz and M. J. Zhu (2009). Maternal over-nutrition and obesity induced inflammatory response in the large intestine of fetal sheep in late gestation. 2009 ADSA-CSAS-ASAS Joint Annual Meeting, Montreal, Quebec, Canada, July 12-16.
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Progress 07/01/09 to 06/30/10
Outputs
OUTPUTS: In pregnant sheep, maternal:fetal exchange occurs across placentomes composed of placental cotyledonary and uterine caruncular tissues. We reported that fetal weights of obese (OB) ewes [fed a diet of 150% of National Research Council (NRC) recommendations] were approximately 30% greater than those of control (C) ewes (fed a diet 100% of NRC recommendations) at midgestation (MG), but fetal weights were similar in late gestation (LG). OB markedly increased (P < 0.05) cholesterol and triglyceride concentrations of both maternal and fetal blood. The mRNA expression of fatty acid transport protein (FATP)1, FATP4, and fatty acid translocase CD (cluster of differentiation) 36 were enhanced in cotyledonary tissue from OB than control ewes, showing that MO altered fatty acid transportation. MO increased mRNA levels of toll-like receptor (TLR) 2 and TLR4, macrophage markers cluster of differentiation (CD)11b, CD14 and CD68, and a number of proinflammatory cytokines in COT tissue. Inflammatory c-Jun N-terminal kinase (JNK)/c-Jun and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathways were up-regulated (P < 0.05) in COT of OB ewes, showing obesity induced inflammation in placenta. Total AMPK and phosphorylated AMPK at Thr 172 (the active form) were reduced (P<0.05) by 19.7+/-8.4% and 25.9+/-7.7%, respectively in the COT arterial tissues of OB ewes. These data in combination show that AMPK activity was down-regulated in OB placenta, which may be associated with enhanced expression of fatty acid transporters and increased fatty acid concentration in OB compared C fetuses. We also conducted another study where multiparous ewes received 100% (control, C, n = 13) or 50% (nutrient restricted, NR, n = 14) of NRC dietary requirements from d28-d78 of gestation. On d78, 5 C and 6 NR ewes were necropsied. The remaining 8 C and 8 NR ewes were fed to 100% of NRC from d78-d135 and necropsied. On d78, but not d135, placental and fetal weights were reduced (P < 0.05) in NR vs. C ewes. Maternal circulating glucose, insulin, and leptin levels were decreased in NR vs. C ewes on d78 (P < 0.05) but similar at d135. Fetal blood glucose and triglyceride levels were lower in NR vs. C ewes (P < 0.05) on d78, but similar on d135. On d78, glucose transporter (GLUT)1, FATP4, CD36 mRNA, and protein expression levels, Fatty acid binding protein mRNA level, and leptin protein level were all increased (P < 0.05) in COT of NR vs. C ewes. AMPK was also increased (P < 0.05) in NR vs. C COT on d78. These data demonstrate placental adaptation to maternal NR through increasing nutrient transporter production and growth signaling activity. PARTICIPANTS: Meijun Zhu, PD devotes 40% effort to this project. Adam Uthlaut, Research Scientist, 30% Collaborator; Stephen P. Ford, Professor, 5% Training or professional development: Yan Ma, Ph.D. student, 50%; Hui Wang, Ph.D. student, 50%. TARGET AUDIENCES: Scientific community. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Placenta mediates nutrient delivery from maternal to fetal circulation, and nutrient availability directly impacts fetal growth and development. Recent studies show that proper fetal development is crucial for the growth performance of offspring. We employed our over-nutrition and under-nutrition models to assess the role of maternal nutrition on placental development, and evaluated the role of AMP-activated protein kinase (AMPK) in placenta development and nutrient transportation. Our data indicated that maternal nutrition has dramatic impact on placental development and cross-placenta nutrient delivery. AMPK was inhibited by maternal over-nutrition but enhanced by maternal under-nutrition, which might have a key role in altered cross-placenta fatty acid and glucose transportation. Knowledge obtained from our studies enhances our understanding of cross-placenta nutritional delivery and the role of AMPK in the regulation of cross-placenta nutrient transportation.
Publications
- Zhu, M. J., Ma, Y. Long, N.M. and Ford, S.P. 2010. Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299: R1224-R12231.
- Zhu, M. J., Du, M. Nathanielsz, P.W. and Ford, S.P. 2010. Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokines expression in the mid-gestation sheep placenta. Placenta. 31: 387-391.
- Ma, Y., Zhu, Uthlaut, A.B. Nijland, M.J. Nathanielsz, P.W. Hess, B.W. and Ford, S.P. 2011. Up-regulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes. Placenta. 32: 255-263.
- Ma. Y., Zhu, M.J., Zhang, L., Hein, S.M., Nathanielsz, P.W. and Ford, S.P. 2010. Maternal obesity and overnurtrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299: R249-R258.
- Yan, X., Huang, Y. Wang, H. Du, M. Hess, B.W., Ford, S.P. and Zhu, M.J. 2011. Maternal obesity induces sustained inflammation in both fetal and offspring large intestine of sheep. Inflammatory Bowel Diseases. PMID: 21113947 (in press)
- Zhu, M.J., Hu, J., Yan, X., Wang, H., Du, M., Hess, B.W. and Ford, S.P. 2011. Maternal obesity induced inflammatory response and increased mast cell density in the ovine fetal ileum at late gestation. International Journal of obesity, submitted.
- Wang, H., Zhao, J., Huang, Y., Yan, X., Meyer, A.M., Du, M., Vonnahme, K., Reynolds, L., Caton J. and Zhu, M.J. 2011. Effects of maternal plane of nutrition and elevated dietary selenium in first parity ewe on inflammatory response in the ovine neonatal gut. Journal of Animal Science. (submitted)
- Wang, H., Zhao, J., Hu, N., Han, X., Ren, J., Du, M. and Zhu, M.J. 2011. Side-stream smoking reduces inflammation and increases the expression of gut tight junction proteins. 111th General Meeting of the American Society for Microbiology, New Orleans, Louisiana, May 21-24, 2011.
- Wang, H., Zhao, J., Huang, Y., Yan, X., Meyer, A.M., Du, M., Vonnahme, K., Reynolds, L., Caton, J. and Zhu, M.J. 2010. Excessive maternal selenium intake induces inflammatory response in the ovine fetal gut. 2010 ADSA-CSAS-ASAS Joint Annual Meeting, Denver, CO, July 11-15.
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Progress 07/01/08 to 06/30/09
Outputs
OUTPUTS: From 60 days before conception to day 75 of gestation, multiparous Rambouillet/Columbia ewes of similar weight and body condition score were placed in individual pens and fed either a highly palatable diet at 100% (control, C; n=10) of National Research Council (NRC) recommendations or 150% (obesogenic, OB; n=10) of NRC recommendations on a metabolic body weight basis (BW0.75) as previously reported. Ewes were weighed at weekly intervals so that individual diets could be recalculated, with rations adjusted for weight gain, and body condition scored at monthly intervals to evaluate changes in fatness. A body condition score of 1 (emaciated) to 9 (obese) was assigned after palpation of the transverse and vertical processes of the lumbar vertebrae (L2 through L5) and the region around the tail head. Ewes were euthanized at day 75 of gestation. Cotyledonary tissue of placentomes was collected for analyses. Fetal weights were ~20% greater (P < 0.05) on OB than C ewes, but birth weights of lambs were similar across dietary groups. Fetal plasma concentrations of glucose, insulin and IGF-1 were higher (P < 0.05) in the blood of fetuses from OB than C ewes. Total AMP-activated protein kinase (AMPK) and phosphorylated AMPK at Thr 172 (the active form) were reduced (P < 0.05) by 19.7% and 25.9%, respectively in the COT arterial tissues of OB ewes. Total acetyl-CoA carboxylase (ACC), a down-stream target of AMPK, and its phosphorylated form were also reduced (P < 0.05) by 32.9% and 45.4%, respectively. The phosphorylation of IRS-1 at Ser 789, a site phosphorylated by AMPK, was 24.5% lower (P < 0.05) in COT arteries of OB than C ewes. No alteration in total insulin receptor, total IGF-1 receptor or their phosphorylated forms was observed, and down-stream insulin signaling was down-regulated in COT arteries of OB ewes, which may have resulted in the observed decrease in COT vascular development in OB ewes. Meanwhile, glucose transporter (Glut) 3 protein content was down-regulated (P<0.05) in COT of OB compared to that of C ewes, while there is no different in Glut1 protein level. PARTICIPANTS: Meijun Zhu, PD devotes 40% effort to this project. Adam Uthlaut, Research Scientist; 30% Collaborator: Stephen P. Ford, Professor, 5% Training or professional development: Nurhan ERTAS, Visiting Scholar Irene C. Steiger, Undergraduate student TARGET AUDIENCES: Target audiences: scientific community PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Placenta mediates nutrient delivery from maternal to fetal circulation, and nutrient availability directly impacts fetal growth and development. Recent studies show that proper fetal development is crucial for the growth performance of offspring. We propose a novel mechanism in the regulation of cross-placental nutrient delivery mediated by AMPK. Our data indicated that AMPK has regulatory roles in the placental functions. Knowledge obtained from our studies will likely provide molecular targets to improve cross-placental nutrient delivery and ensure proper fetal development, improving growth performance of progeny.
Publications
- Zhu, M.J., Du, M., Nijland, M.J., Nathanielsz, P.W., Hess, B.W., Moss, G.E., Ford, S.P. 2009. Down-regulation of growth signaling pathways linked to a reduced cotyledonary vascularity in placentomes of overnourished, obese pregnant ewes. Placenta 30: 405-410.
- Zhu, M.J., Du, M., Nathanielsz, P.W., Ford, S.P. 2009. Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in sheep placenta at mid-gestation. Placenta submitted.
- Zhu, M.J., Du, M., Tong, C., Hess, B.W., Ford, S.P. and Nathanielsz, P.W. 2009. Maternal over-nutrition and obesity induced inflammatory response in the fetal ileum of sheep Society for the Study of Reproduction 42nd annual meeting, Pittsburgh, Pennsylvania, July 18-22.
- X. Yan, Du, M. Bret, B.W., Ford, S.P., Nathanielsz, P.W. and Zhu, M.J. 2009. Maternal over-nutrition and obesity induced inflammatory response in the large intestine of fetal sheep in late gestation. 2009 ADSA-CSAS-ASAS Joint Annual Meeting, Montreal, Quebec, Canada, July 12-16.
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