Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (Adenosine monophosphate (AMP)-activated protein kinase), mTOR (Mechanistic Target of Rapamycin), and Insulin/IGF1 (Insulin-like Growth Factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways, and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n=17), AGA (n=19) and LGA (n=10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and Insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1 correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in pIGF1R, INSRb, total Akt or pAkt were found, pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and thus, long-term metabolic health.

Adverse environmental factors in early life result in fetal metabolic programming and increased risk of adult diseases. Birth weight is an indirect marker of the intrauterine environment, modulated by nutrient availability and placental transport capacity. However, studies of placental transporters in idiopathic birth weight alterations and in maternal obesity in relation to neonatal metabolic outcomes are scarce. We aimed to analyze the placental nutrient transporter protein expression in small (SGA, n = 14), adequate (AGA, n = 18), and large (LGA n = 10) gestational age term for newborns from healthy or obese mothers (LGA-OB, n = 9) and their association with maternal fatty acids, metabolic status, placental triglycerides, and neonatal outcomes. The transporter expression was determined by Western blot. The fatty acid profile was evaluated by gas chromatography, and placental triglycerides were quantified by an enzymatic colorimetric method. GLUT1 was higher in LGA and lower in SGA and positively correlated with maternal HbA1c and placental weight (PW). SNAT2 was lower in SGA, while SNAT4 was lower in LGA-OB. FATP1 was lower in SGA and higher in LGA. SNAT4 correlated negatively and FATP1 correlated positively with the PW and birth anthropometry (BA). Placental triglycerides were higher in LGA and LGA-OB and correlated with pregestational BMI, maternal insulin, and BA. Maternal docosahexaenoic acid (DHA) was higher in SGA, specifically in male placentas, correlating negatively with maternal triglycerides, PW, cord glucose, and abdominal perimeter. Palmitic acid (PA) correlated positively with FATP4 and cord insulin, linoleic acid correlated negatively with PA and maternal cholesterol, and arachidonic acid correlated inversely with maternal TG and directly with FATP4. Our study highlights the importance of placental programming in birth weight both in healthy and obese pregnancies.

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