Effect of Leptin on Mouse Trophoblast Giant Cells1

Abstract

Leptin plays a role in both energy homeostasis and reproduction, and it is required in early pregnancy. It stimulates metalloproteinase activity in cultured human trophoblasts and invasiveness of cultured mouse trophoblasts. Our goal has been to examine mechanisms that underpin the ability of leptin to promote trophoblast invasiveness in primary cultures of mouse trophoblasts. Leptin stimulated the phosphorylation of MEK (MAP2K1) but not signal transducer and activator of transcription 3 (STAT3) in the cultures, increased the concentration of the suppressor of cytokine signaling 3 (SOCS3) protein, and upregulated metalloproteinase activity. Microarray analysis revealed that leptin stimulated select genes with roles in cell motility, including Stmn, a gene linked to invasiveness in other cell types. There was also an increase in activity of several genes associated with MAPK and RhoGTPase signaling. In addition, leptin muted expression of genes correlated with terminal differentiation of trophoblast giant cells, including ones associated with the TGFbeta signaling pathway and endoreduplication of DNA, and upregulated selected prolactin-related family members. Feulgen staining of leptin-treated cells revealed a loss of cells with low ploidy. The data suggest that leptin accelerates disappearance of non-giant cells while inhibiting terminal differentiation of committed giant cells, possibly by maintaining cells in an intermediate stage of differentiation.

Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction

“…This was not due to a sampling error caused by controlling our cohort to exclude extremes of litter size and genotype ratio, as when we pooled the data for all crosses generated, Null females consistently produced approximately one additional conceptus compared with WT or Mat females (WT and Mat mean litter size = 7.0 ± 0.3, n = 40 litters; Null mean litter size 8.2 ± 0.3, n = 48 litters, p < 0.001, Mann Whitney test). Appropriate maternal leptin levels are necessary for conception and survival of the early embryo[16]; leptin increases the invasiveness of the early embryo[17] and enhances ovulation[18]. Our finding that Null females had increased fecundity is consistent with their elevated leptin levels (Supplementary Fig.…”

The source of leptin, but not leptin depletion in response to food restriction, changes during early pregnancy in mice

“…Adult health has been shown to be particularly vulnerable to programming by food restriction during early pregnancy. Because leptin influences such variables as embryo implantation [12], placental cell differentiation [50] and placental amino acid transport [51], as well as fetal muscle and skeletal development [13,14] the shortage of leptin following food restriction that we have demonstrated here is worthy of future study as one route by which by which food restriction exerts its effects.…”

Genes and signals regulating murine trophoblast cell development

“…Furthermore a recent study by Schulz et al (2009) suggested that leptin influences TGC differentiation. Leptin accelerates disappearance of non-giant cells while inhibiting terminal differentiation of committed giant cells, possibly by maintaining cells in an intermediate stage of differentiation.…”