Chaperon mediated autophagy in placentas of obese women: a pilot study

Introduction: Maternal obesity (OB) represents a significant risk factor for both adverse pregnancy and long-term outcomes. We recently showed altered placental mitochondria in OB, suggesting increased oxidative stress. Chaperone mediated autophagy (CMA) is a specific form of autophagy activated by oxidative stress, interacting with macroautophagy in a mutual modulation, for the maintenance of cell homeostasis. CMA activity results in important changes in cell energetics and metabolism. Here we hypothesized altered CMA activity in OB placentas. Methods: We measured gene expression of the CMA activator PHLPP1 in placentas delivered by elective caesarean section of normal weight (NW, n=5) and OB women (healthy n=5; with GDM, diet-treated n=5). Cesarean sections before labor were performed for breech presentation, repeated caesarean section, or maternal request. RNA levels were analyzed by Real Time PCR, using Beta Actin for data normalization. Statistics: independent-samples t-test, Levene’s test for equality of variances. Data were considered significant when p<0.05. Results: All women delivered at term, appropriate for gestational age babies. Placental weight was higher (p=0.01), and placental e!ciency (fetal/placental weight) was lower in OB vs NW (p=0.005). All patients were no smokers. OB placentas showed significantly increased PHLPP1 mRNA levels vs NW (p=0.03). Interestingly, OB+GDM placentas had higher PHLPP1 gene expression compared to healthy OB, though not significantly. Conclusion: There are few reports correlating autophagy to obesity, suggesting autophagy activation in the obese omental and subcutaneous adipose tissues. However, the role of autophagy in human placentas remains controversial. In particular, only few contrasting studies in OB/GDM placentas reported alterations of macroautophagy, but to date placental CMA activity has never been specifically investigated. Increased PHLPP1 expression concurs at CMA induction. The excessive mitochondrial ROS release previously showed in OB placentas might induce abnormal upregulation of CMA activity. In turn, increased CMA activity was shown to alter cellular energetics by degradation of key metabolism enzymes. In this scenario, CMA could represent an interesting regulatory mechanism linking the intrauterine obese environment with placental dysfunction, leading to less e!cient placentas and possible later disease. The role of increased PHLPP1 in relation to the modulation of CMA activity in OB placentas, still remains to be defined. Further analyses are in progress to confirm our preliminary results.