Chronic maternal infusion of full‐length adiponectin in pregnant mice down‐regulates placental amino acid transporter activity and expression and decreases fetal growth

Key points • Fetal growth is positively correlated to maternal adiposity, but the underlying mechanisms remain largely unknown. • Maternal circulating levels of adiponectin, a hormone secreted by adipose tissue, are negatively correlated to maternal adiposity and fetal growth, suggesting that maternal adiponectin may limit fetal growth. • Here we report that chronic administration of adiponectin to pregnant mice inhibits placental insulin and mammalian target of rapamycin (mTOR) signalling, down‐regulates the activity and expression of key placental nutrient transporters, and decreases fetal growth. • We have identified a novel physiological mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth by altering placental function. • These findings may help us better understand the factors determining birth weight in normal pregnancies and in pregnancy complications associated with altered maternal adiponectin levels such as obesity and gestational diabetes. Maternal adiponectin levels are inversely correlated to birth weight, suggesting that maternal adiponectin limits fetal growth. We hypothesized that full‐length adiponectin (fADN) infusion in pregnant mice down‐regulates placental amino acid transporters and decreases fetal growth. Starting at embryonic day (E) 14.5, fADN (0.62 ± 0.02 μg (g body weight)−1 day−1, n= 7) or vehicle (control, n= 9) were infused in pregnant C57/BL6 mice by mini‐osmotic pump. At E18.5, dams were killed and placental homogenates and trophoblast plasma membrane (TPM) vesicles were prepared. Infusion of fADN elevated maternal serum fADN by 4‐fold and decreased fetal weights by 18%. Adiponectin receptor 2, but not adiponectin receptor 1, was expressed in TPM. fADN infusion decreased TPM System A (–56%, P < 0.001) and System L amino acid transporter activity (–50%, P < 0.03). TPM protein expression of SNAT1, 2 and 4 (System A amino acid transporter isoforms) and LAT1 and LAT2, but not CD98, (System L amino acid transporter isoforms) was down‐regulated by fADN infusion. To identify possible mechanisms underlying these changes we determined the phosphorylation of proteins in signalling pathways known to regulate placental amino acid transporters. fADN decreased phosphorylation of insulin receptor substrate‐1 (Tyr‐608), Akt (Thr‐308 and Ser‐473), S6 kinase 1 (Thr‐389), eukaryotic initiation factor 4E binding protein 1 (Thr‐37/46 and Thr‐70) and ribosomal protein S6 (Ser‐235/236) and increased