Vitamin D Supplementation Improves Mitochondrial Function and Reduces Inflammation in Placentae of Obese Women

Abstract

BackgroundAbout 30% of women entering pregnancy in the US are obese. We have previously reported mitochondrial dysregulation and increased inflammation in the placentae of obese women. Vitamin D (VitD) is a major player in calcium uptake and was shown to modulate mitochondrial respiration and the immune/inflammation system. Studies show decreased VitD levels in obese individuals; however, the effect of maternal obesity on VitD metabolism and its association with placental function remains understudied.MethodsMaternal and cord blood plasma and placental samples were collected upon C-section from normal-weight (NW, body mass index [BMI]<25) and obese (OB, BMI>30) women with uncomplicated pregnancies at term. We measured 25(OH)D3 (calcidiol) levels in maternal and cord blood plasma using ELISA. We assessed the expression of CYP27B1, an activator of calcidiol, and Vitamin D receptor (VDR) in placentae from NW and OB, and women with gestational diabetes and preeclampsia. In addition, we examined the effects of VitD supplementation on mitochondrial function and inflammation in trophoblasts from NW and OB, using the Seahorse Bioanalyzer and Western blot, respectively.ResultsVitamin D levels in blood from OB but not NW women and in cord blood from babies born to NW and OB women showed a significant inverse correlation with maternal pre-pregnancy BMI (r=-0.50, p<0.1 and r=-0.55, p=0.004 respectively). Cord plasma VitD levels showed a positive correlation with placental efficiency, i.e., the ratio between fetal and placental weight, as well as with maternal blood VitD levels (r=0.69 and 0.83 respectively, p<0.00). While we found no changes in CYP27B1 in OB vs. NW women, VDR expression were decreased by 50% (p<0.03) independent of fetal sex. No changes in VDR expression relative to BMI-matched controls were observed in the placentae of women with gestational diabetes or preeclampsia. Cytotrophoblasts isolated from placentae of OB women showed a dose-dependent increase in VDR expression after 24-hour treatment with calcitriol (10 nM and 100 nM), an active form of VitD. Trophoblasts isolated from OB women and treated with calcitriol improved mitochondrial respiration (p<0.05). We also found a two-fold increase in expression of the NLRP3 inflammasome and the pro-inflammatory cytokine IL-18 in trophoblasts isolated from placentae of OB women (p<0.05), with IL-18 expression being reversed by calcitriol treatment (100 nM).ConclusionsWe show that VitD deficiency is at least partially responsible for mitochondrial dysfunction and increased inflammation in the placentae of obese women. Vitamin D supplementation could be beneficial in improving placental dysfunction seen in obese women.

Vitamin D-VDR (vitamin D receptor) alleviates glucose metabolism reprogramming in lipopolysaccharide-induced acute kidney injury

“…This runaway reprogramming of glucose metabolism can be restored by paricalcitol, a VDR agonist. VDR can inhibit glycolysis in colorectal cancer (Zuo et al, 2020), and VD supplementation can improve mitochondrial respiration in primary trophoblasts isolated from obese women (Phillips et al, 2022) In our animal experiments, we confirmed the regulatory effect of VDR on p-PDHA1; however, the specific regulatory mechanism is still unclear. PDHA1 is a key site regulating PDHc, and its phosphorylation is involved in the pathological mechanism of many diseases.…”

The Effects of Latitude and Temperate Weather on Vitamin D Deficiency and Women's Reproductive Health: A Scoping Review

“…This study, done in Oregon in the United States (45° N), showed that vitamin D deficiency is, at least partially, responsible for mitochondrial dysfunction and increased placental inflammation among women with obesity. Therefore, receiving adequate amounts of vitamin D is very important to maintain normal placental function 34 in the context of maternal obesity 35 . Based on findings from a clinical trial of vitamin D supplementation during pregnancy, the authors suggested increased supplementation doses of vitamin D for pregnant women who had vitamin D insufficiency in early pregnancy, higher pregnancy weight gain, or an expected birth during the winter 32 …”

“…Obesity and low vitamin D concentrations among pregnant women are associated with newborns having low vitamin D concentrations at birth 33 . A recent study showed that low vitamin D levels in umbilical cord blood among women with obesity were correlated with a decreased ratio between fetal and placental weights, an indicator of placental insufficiency 35 . This suggests that placental transfer of vitamin D is impaired in women with obesity, explaining the lower levels of vitamin D in their newborns.…”

Comparison of the anti‑inflammatory effects of vitamin E and vitamin D on a rat model of dextran sulfate sodium‑induced ulcerative colitis

“…In addition, vitamin D has been shown to prevent osteoporosis in the elderly, while it increases resistance to COVID-19 in appropriate concentrations ( 35 ). In women and children, vitamin D deficiency can lead to placental dysgenesis, affecting the innate development and immunity of infants and children ( 32 , 35 , 37 ).…”

“…Furthermore, vitamin D can change the composition of the intestinal flora through regulation of the expression of antibacterial peptides, in addition to immune regulation ( 31 ). Phillips et al ( 32 ) demonstrated that vitamin D may provide some protection against increased mitochondrial dysfunction and inflammation in the placenta of obese women. In addition, Hahn et al ( 33 ) indicated that long-term vitamin D supplementation may be effective for reducing the incidence of autoimmune diseases.…”