Kelly, A., Bidwell, C., Chen, X., Anderson, M., & Limesand, S. (2016). Identifying the Adrenergic Component of Intrauterine Growth Restriction in Fetal Pancreatic beta-Cells.. REPRODUCTIVE SCIENCES, 23, 94A-94A.
Brown, L. D., Davis, M., Wai, S., Wesolowski, S. R., Hay Jr., W. W., Limesand, S. W., & Rozance, P. J. (2016). Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep. ENDOCRINOLOGY, 157(10), 3788-3799.
Yates, D. T., Cadaret, C. N., Beede, K. A., Riley, H. E., Macko, A. R., Anderson, M. J., Camacho, L. E., & Limesand, S. W. (2016). Intrauterine growth-restricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term. American journal of physiology. Regulatory, integrative and comparative physiology, 310(11), R1020-9.
Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fiber-type ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers. Placental insufficiency-induced IUGR fetuses were ∼54% smaller (P 0.05) than controls and exhibited hypoxemia and hypoglycemia, which contributed to 6.9-fold greater (P 0.05) plasma norepinephrine and ∼53% lower (P 0.05) plasma insulin concentrations. IUGR semitendinosus muscles contained less (P 0.05) myosin heavy chain-I protein (MyHC-I) and proportionally fewer (P 0.05) Type I and Type I/IIa fibers than controls, but MyHC-II protein concentrations, Type II fibers, and Type IIx fibers were not different. IUGR biceps femoris muscles exhibited similar albeit less dramatic differences in fiber type proportions. Type I and IIa fibers are more responsive to adrenergic and insulin regulation than Type IIx and may be more profoundly impaired by the high catecholamines and low insulin in our IUGR fetuses, leading to their proportional reduction. In both muscles, fibers of each type were uniformly smaller (P 0.05) in IUGR fetuses than controls, which indicates that fiber hypertrophy is not dependent on type but rather on other factors such as myoblast differentiation or protein synthesis. Together, our findings show that IUGR fetal muscles develop smaller fibers and have proportionally fewer Type I fibers, which is indicative of developmental adaptations that may help explain the link between IUGR and adulthood insulin resistance.
Frost, M., Zehri, A., Limesand, S., Hay, J. W., & Rozance, P. (2012). Differential effects of chronic pulsatile vs. chronic constant maternal hyperglycemia on fetal pancreatic beta-cells. Journal of Pregnancy.
Article ID 812094, 2012
Limesand, S. W., & Anthony, R. V. (2001). Novel activator protein-2α splice-variants function as transactivators of the ovine placental lactogen gene. European Journal of Biochemistry, 268(8), 2390-2401.
PMID: 11298758;Abstract:
Activator protein-2 (AP-2) has been implicated as a transactivator of the human and ovine placental lactogen (oPL) genes. Transcriptional enhancement through an AP-2 cis-acting element has been described for other genes expressed in the placenta, but the AP-2 isoform enhancing expression is species dependent. Transactivation of the oPL minimal promoter (-124 bp to +16 bp) by AP-2 was confirmed by mutational analysis in transiently transfected human choriocarcinoma cells (BeWo). AP-2α was localized in ovine chorionic epithelial cells by immunohistochemistry and a 3-kb transcript was identified by Northern hybridization. Four nearly full-length AP-2 cDNAs were isolated from an ovine placenta cDNA library. Nucleotide sequencing these cDNAs revealed that the AP-2 mRNA expressed in the ovine placenta shares identity with human AP-2α, but variations in the predicted N-terminus were observed, and three unique AP-2α splice-variants were identified. Expression of AP-2α variants in HepG2 cells, devoid of endogenous AP-2, indicates that enhancement through the AP-2 element in the oPL gene minimal promoter was variant dependent. RNA transcripts for all of the ovine AP-2α splice-variants were confirmed in ovine placenta by RT-PCR, and homologs for two variants were found in human placenta. However, only one AP-2α transcript, which shares identity to Xenopus AP-2α, was expressed in BeWo cells. Immunoblot analysis confirmed AP-2α variants in ovine chorionic binucleate cell nuclear extracts, one of which migrates similar to the AP-2α variant identified in BeWo cell nuclear extracts. These data indicate the presence of new mammalian AP-2α splice-variants that augment transactivation of the oPL gene in ovine chorionic binucleate cells.