Chorionic somatomammotropin RNA interference alters fetal liver glucose utilization

Area of Science:

• Reproductive biology and endocrinology
• Fetal development and metabolism
• Genomics and molecular biology

Background:

• Chorionic somatomammotropin (CSH) is a crucial placenta-specific hormone regulating fetal growth and metabolism in sheep and humans.
• Understanding CSH's role is vital for addressing fetal growth disorders and metabolic complications during pregnancy.
• CSH deficiency's specific impact on fetal liver glucose utilization remains largely uncharacterized.

Purpose of the Study:

• To investigate the hypothesis that Chorionic somatomammotropin (CSH) deficiency affects sheep fetal liver glucose utilization.
• To analyze the molecular and metabolic consequences of CSH deficiency in ovine fetal livers.
• To differentiate the direct effects of CSH deficiency from indirect effects mediated by intrauterine growth restriction (IUGR).

Main Methods:

• Generation of CSH-deficient ovine pregnancies using lentiviral vectors expressing CSH-specific shRNA (RNAi) or control shRNA (SC).
• Phenotypic classification of pregnancies at 135 days gestational age into intrauterine growth restriction (RNAi-IUGR) or normal weight (RNAi-NW) groups.
• Analysis of fetal body, liver, and placental weights, plasma hormone concentrations (insulin, IGF1), fetal liver gene/protein expression (INSR, IGFs, IGFBPs, GYS1, LDHB), and glycogen content.

Main Results:

• CSH RNAi induced two phenotypes: RNAi-IUGR with reduced fetal and placental weights, and RNAi-NW with normal fetal weight.
• Both RNAi phenotypes exhibited decreased plasma insulin and IGF1, increased fetal liver INSR, and altered IGF signaling (IGF1, IGF2, IGFBP2, IGFBP3 mRNA).
• CSH deficiency led to increased fetal liver glycogen storage and GYS1 activity, with reduced LDHB in RNAi-IUGR fetuses, suggesting altered glucose metabolism.

Conclusions:

• CSH deficiency impacts ovine fetal liver glucose utilization independently of IUGR, indicated by enhanced glycogen synthesis and altered insulin sensitivity.
• The findings highlight a direct role for CSH in regulating fetal glucose metabolism, potentially through modulation of insulin signaling pathways.
• Further research is needed to elucidate the precise mechanisms and physiological significance of these CSH-dependent metabolic adaptations in fetal development.