Trophectoderm-specific RNA interference of chorionic somatomammotropin alters glucose metabolism in sheep fetal liver

Chorionic somatomammotropin (CSH) is a placentaspecific hormone and secreted into both fetal and maternal circulation. Reduced maternal CSH is observed with intrauterine growth restriction (IUGR) in both humans and sheep, and it has long been held that CSH modulates maternal and fetal metabolism. We hypothesized that CSH deficiency, created by RNA interference (RNAi), could impact fetal liver glucose metabolism. To generate CSH-deficient pregnancies, day 9 hatched blastocysts were infected with lentiviral particles expressing CSH-specific shRNA (RNAi) or scramble control shRNA (SC) and transferred to synchronized recipients. CSH RNAi generated two distinct phenotypes at 135 dGA; CSH RNAi pregnancies with IUGR (RNAi-IUGR; n = 8) or without IUGR (RNAi; n = 8). Data from both RNAi phenotypes were compared separately with SC using Welchs t-test. Liver and placental weights were reduced (P < 0.05) in RNAi-IUGR pregnancies, but not in RNAi pregnancies, as compared to SC (n = 8). Umbilical artery plasma insulin and insulin-like growth factor 1 (IGF1) concentrations were decreased (P < 0.05), whereas insulin receptor beta (IRß) concentration, as determined by Western immunoblot analysis, in fetal liver was increased (P < 0.05) in both RNAi phenotypes. Fetal liver glycogen quantity was also increased (P < 0.05) in both RNAi phenotypes. Glycogen synthase-1 (GYS-1) concentration in fetal liver was increased (P < 0.05) in both RNAi phenotypes, whereas there was no change in GYS-2 concentration. Phosphorylated-GYS (inactive GYS) was reduced (P < 0.05) in fetal livers for both RNAi phenotypes. Lactate dehydrogenase beta (LDHß) concentration was increased (P < 0.05) and IGF2 concentration was decreased (P < 0.05) in RNAiIUGR fetal livers only. From these results we conclude that fetal liver glucose metabolism is impacted by CSH RNAi, independent of IUGR, and is likely tied to enhanced insulin sensitivity in both CSH RNAi phenotypes. Differences between the two phenotypes may help differentiate direct and indirect effects of CSH. Supported by NIH R01 HD093701.