Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity

22 Fetal overgrowth is common in obese women and is associated with perinatal complications and 23 increased risk for the child to develop metabolic syndrome later in life. Placental nutrient 24 transport capacity has been reported to be increased in obese women giving birth to large infants, 25 however the underlying mechanisms are not well established. Obesity in pregnancy is 26 characterized by elevated maternal serum insulin and leptin, hormones that stimulate placental 27 amino acid transporters in vitro. We hypothesized that maternal obesity activates placental 28 insulin/IGF-I/mTOR and leptin signaling pathways. We tested this hypothesis in a mouse model 29 of obesity in pregnancy that is associated with fetal overgrowth. C57BL/6J female mice were 30 fed a control (C) or a high fat/high sugar (HF/HS) pelleted diet supplemented by ad libitum 31 access to sucrose (20%) solution. Placentas were collected at embryonic day 18.5. Using 32 Western blot analysis, placental mTOR activity was determined along with energy, 33 inflammatory, leptin and insulin signaling pathways (upstream modulators of mTOR). 34 Phosphorylation of S6 ribosomal protein (S-235/236), 4E-BP1 (T-37/46), IRS-1 (Y-608), Akt 35 (T-308) and STAT-3 (Y-705) was increased in obese dams. In contrast, expression of placental 36 caspase-1, IкBα, IL-1β and phosphorylated-JNK p46/54 T183/Y185 was unaltered. Fetal amino acid 37 availability is a key determinant of fetal growth. We propose that activation of placental 38 insulin/IGF-I/mTOR and leptin signaling pathways in obese mice stimulates placental amino 39 acid transport and contributes to increased fetal growth. 40