Knockout maternal adiponectin increases fetal growth in mice: potential role for trophoblast IGFBP-1

Abstract

Aims/hypothesis The main objective of this study was to investigate whether maternal adiponectin regulates fetal growth through the endocrine system in the fetal compartment. Methods Adiponectin knockout (Adipoq−/−) mice and in vivo adenovirus-mediated reconstitution were used to study the regulatory effect of maternal adiponectin on fetal growth. Primary human trophoblast cells were treated with adiponectin and a specific peroxisome proliferator-activated receptor α (PPARα) agonist or antagonist to study the underlying mechanism through which adiponectin regulates fetal growth. Results The body weight of fetuses from Adipoq−/− dams was significantly greater than that of wild-type dams at both embryonic day (E)14.5 and E18.5. Adenoviral vector-mediated maternal adiponectin reconstitution attenuated the increased fetal body weight induced by maternal adiponectin deficiency. Significantly increased blood glucose, triacylglycerol and NEFA levels were observed in Adipoq−/− dams, suggesting that nutrient supply contributes to maternal adiponectin-regulated fetal growth. Although fetal blood IGF-1 concentrations were comparable in fetuses from Adipoq−/− and wild-type dams, remarkably low levels of IGF-binding protein 1 (IGFBP-1) were observed in the serum of fetuses from Adipoq−/− dams. IGFBP-1 was identified in the trophoblast cells of human and mouse placentas. Maternal fasting robustly increased IGFBP-1 levels in mouse placentas, while reducing fetal weight. Significantly low IGFBP-1 levels were found in placentas of Adipoq−/− dams. Adiponectin treatment increased IGFBP-1 levels in primary cultured human trophoblast cells, while the PPARα antagonist, MK886, abolished this stimulatory effect. Conclusions/interpretation These results indicate that, in addition to nutrient supply, maternal adiponectin inhibits fetal growth by increasing IGFBP-1 expression in trophoblast cells.

Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring

“…Indeed, chronic infusion of full-length ADN to normal-weight pregnant mice decreased fetal weight, demonstrating that maternal ADN limits fetal growth (34). This conclusion was recently confirmed in elegant studies in which knockdown of the maternal ADN gene resulted in increased fetal growth (35,36). We have further demonstrated that ADN regulates placental function mediated by activation of trophoblast peroxisome proliferator-activated receptor a (PPAR-a) signaling, which increases ceramide synthesis resulting in inhibition of insulin receptor substrate 1 (IRS-1) (33).…”

Mechanisms of Adiponectin Action in Fertility: An Overview from Gametogenesis to Gestation in Humans and Animal Models in Normal and Pathological Conditions

“…The body weight of foetuses from adiponectin (−/−) dams was significantly greater than that of wild type dams at both embryonic day (E)14.5 and (E)18.5. In addition to nutrient supply, maternal adiponectin inhibits foetal growth by increasing IGFBP-1 expression in trophoblast cells [143].…”

The Relationship between Maternal Plasma Leptin and Adiponectin Concentrations and Newborn Adiposity

“…Analysis of fetal weight and body composition showed that the maternal high-fat diet increased the weight and fat mass of offspring of WT dams, while the offspring of knockout dams had a lower weight and fat mass. In a recent study [13], the offspring of adiponectin gene–knockout dams exhibited a greater weight and fat mass than WT offspring. Furthermore, chronic infusion of adiponectin in pregnant mice has been shown to decrease fetal growth, possibly by reducing amino acid transporter activity and expression [14].…”