Placental Antioxidant Defenses and Autophagy-Related Genes in Maternal Obesity and Gestational Diabetes Mellitus

Abstract

Maternal obesity and gestational diabetes mellitus (GDM) are increasing worldwide, representing risk factors for both mother and child short/long-term outcomes. Oxidative stress, lipotoxicity and altered autophagy have already been reported in obesity, but few studies have focused on obese pregnant women with GDM. Antioxidant and macro/chaperone-mediated autophagy (CMA)-related gene expressions were evaluated herein in obese and GDM placentas. A total of 47 women with singleton pregnancies delivered by elective cesarean section were enrolled: 16 normal weight (NW), 18 obese with no comorbidities (OB GDM(–)), 13 obese with GDM (OB GDM(+)). Placental gene expression was assessed by real-time PCR. Antioxidant gene expression (CAT, GPX1, GSS) decreased, the pro-autophagic ULK1 gene increased and the chaperone-mediated autophagy regulator PHLPP1 decreased in OB GDM(–) vs. NW. On the other hand, PHLPP1 expression increased in OB GDM(+) vs. OB GDM(–). When analyzing results in relation to fetal sex, we found sexual dimorphism for both antioxidant and CMA-related gene expressions. These preliminary results can pave the way for further analyses aimed at elucidating the placental autophagy role in metabolic pregnancy disorders and its potential targetability for the treatment of diabetes outcomes.

Role of Inflammaging on the Reproductive Function and Pregnancy

“…In detail, both inflammation and premature aging have been related to placental dysfunction, leading to pregnancy pathologies and adverse pregnancy outcomes, with shortand long-term consequences in the offspring [6,[70][71][72]. Inflammation can generate oxidative stress and vice versa, in a negative vicious cycle leading to alterations in cell metabolism.…”

“…Maternal malnutrition, in terms of both nutrients excess and deficiency, has been reported as one of the most impacting factors on placental altered function and bioenergetics [70,71,[74][75][76]. Indeed, it generates a lipotoxic intrauterine environment increasing inflammation, oxidative stress and cell senescence [76,77].…”

The Sexually Dimorphic Nature of the Human Placenta: A Literature Review

“…Placental efficiency is an important indicator of placental function in humans and is calculated as fetal weight divided by placental weight. Low placental efficiency values are due to decreased transportation of nutrients or failure to adapt and are associated with fetal growth restriction whereas high placental efficiency values are indicative of greater nutrient transport and hence average sized fetuses [27]. In 2021, Diceglie et al found that obese women, whether having the comorbidity of GDM or not, often had lower placental efficiencies than women who were considered to have normal weight with no GDM [27].…”

“…Low placental efficiency values are due to decreased transportation of nutrients or failure to adapt and are associated with fetal growth restriction whereas high placental efficiency values are indicative of greater nutrient transport and hence average sized fetuses [27]. In 2021, Diceglie et al found that obese women, whether having the comorbidity of GDM or not, often had lower placental efficiencies than women who were considered to have normal weight with no GDM [27]. When comparing the three groups under investigation (normal weight, obese and no GDM, obese with GDM), placental efficiency gradually decreased as the number of comorbidities increased.…”

“…When comparing the three groups under investigation (normal weight, obese and no GDM, obese with GDM), placental efficiency gradually decreased as the number of comorbidities increased. Fetal sex was determined to impact "placental biometrical and functional features," namely placental efficiency [27]. Female fetuses whose mothers were both obese and suffered from GDM had decreased placental efficiency compared to their male counterparts.…”