Maternal obesity activates placental mTOR signaling and increases fetal growth in rats

GACCIOLI F; WHITE V; JAWERBAUM A; POWELL TL; JANSSON T

Orlando

Congreso; Society for Gynecologic Investigation (SGI); 2013

OBJECTIVES: Obese women have a high dietary fat intake and an increased risk of giving birth to a large baby. The mammalian target of rapamycin (mTOR) pathway functions as a placental nutrient sensor and is a positive regulator of placental growth and nutrient transport. We hypothesized that maternal obesity induced by a high fat diet up-regulates placental mTOR signaling and nutrient transport, resulting in fetal overgrowth. METHODS: Albino Wistar female rats were fed a standard chow +/- saturated animal fat for 6 weeks before mating and throughout pregnancy. Dams were sacrificed at gestational day (GD) 21 (N=9 control diet, C; N=10 high fat diet, HF) and maternal and fetal blood were collected. Total placental homogenates were prepared for Western blot analysis and isolation of trophoblast plasma membranes (TPM). Phosphorylation of placental 4EBP1 and rpS6 was determined to evaluate mTOR Complex 1 (mTORC1) activity, and placental expression of P-Akt (T308, S473), P-AMPK (T172) and P-ERK1/2 (T202/Y204) were measured to study signaling upstream of mTOR. We determined P-JNK (T183/Y185), P-STAT3 (T705), total I and cleaved Caspase 1 as readouts of placental inflammation. Furthermore, System A and L transport activity, and the expression of SNAT1, 2, 4 and GLUT1, 3, 9 proteins were measured in TPM. RESULTS: The HF-diet significantly increased maternal and fetal serum triglyceride levels (+118% and +35%, respectively) but not maternal glycemia. Both maternal (+20%, P<0.01) and fetal weights (+6%, P<0.05) were increased at GD21 and placental weight was trending towards an increase (P=0.14). Placental expression of P-4EBP1 (T36/47) (+39%, P<0.05) and P-rpS6 (S235/236) (+48%, P=0.07) was increased and P-AMPK significantly reduced (-28%, P<0.01) in the HF-group. Phosphorylation of 4EBP1 (T70), Akt, ERK1/2, JNK, STAT3 and expression of I and cleaved Caspase 1 were not different between groups. The HF-diet did not significantly affect SNAT and GLUT isoform expression and System A and L amino acid transport activity in TPM. CONCLUSION: Diet induced obesity in the rat activates placental mTORC1, possibly through the inhibition of AMPK signaling. We speculate that mTOR up-regulation stimulates placental growth and therefore the overall nutrient transport capacity, contributing to the higher fetal weights observed in the HF-group