Placental energy metabolism in health and disease—significance of development and implications for preeclampsia

Aye, Irving L.M.H.; Aiken, Catherine; Charnock‐Jones, D. Stephen; Smith, Gordon C. S.

doi:10.1016/j.ajog.2020.11.005

Cited by 87 publications

(84 citation statements)

References 132 publications

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“…Metformin is also prescribed for other indications, including polycystic ovary syndrome (PCOS) [8], gestational diabetes [9] and obesity [10], although these uses are not licensed in the UK or USA. A mounting body of evidence also suggests that metformin may be of benefit in diverse conditions such as cancer treatment [11], dermatological conditions [12], preeclampsia [13] and osteoarthritis [14].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis

et al. 2021

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Introduction: Metformin is among the most frequently prescribed drugs worldwide for a variety of indications. Although metformin has several important advantages, for example being easy to store and administer, it is associated with a high incidence of gastrointestinal side effects. Slower-release formulations of metformin may reduce the incidence of side effects while maintaining efficacy; however, there is a lack of systematic evidence available to guide head-to-head comparisons between different metformin formulations.Methods: PubMed, Web of Science, OVID EMBASE, MEDLINE, The Cochrane database and Clinicaltrials.gov were systematically searched (from inception to 25 January 2021). Trials that randomized adult participants to extendedrelease formulation of metformin (met-XR), delayed-release (met-DR) or immediate-release metformin (met-IR) were included. Two reviewers independently assessed articles for eligibility and risk-of-bias, with conflicts resolved by a third reviewer. Outcome measures were change in fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), body weight, BMI, lipid profile and side effects. Meta-analyses were conducted using random-effects models. Results: Fifteen studies (n = 3765) met eligibility criteria. There was no significant difference between the efficacy of met-IR, met-XR or met-DR in changing FPG (p = 0.93). A non-significant reduction in mean body weight was observed in individuals randomized to met-XR vs. met-IR (-1.03 kg, 95% CI -2.12 to 0.05, p = 0.06). Individuals randomized to met-XR vs. met-IR had lower low-density lipoprotein (LDL) cholesterol levels (-5.73 mg/dl, 95% CI -7.91 to -3.56, p \ 0.00001). Gastrointestinal (GI) side effects were markedly reduced in patients randomised to met-DR vs. met-IR (OR 0.45, 95% CI 0.26-0.80, p = 0.006). Conclusion:Our results demonstrate equal efficacy of longer-acting formulations (met-XR, met-DR) versus immediate-release metformin formulations in terms of glycaemic control.

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Section: Introductionmentioning

confidence: 99%

Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis

et al. 2021

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“…But until now, very little research has focused on the glycolytic capacities in the preeclamptic placentas. Metabolomic analysis has found the upregulated concentration of the glycolytic product (lactate and pyruvate) [ 59 , 60 ] in the serum from PE women, which impaired OXPHOS capacity while enhanced glycolysis in trophoblasts, resulting in a weak ATP synthesis [ 61 ] owing to the lower efficiency of glycolysis [ 20 ]. PE mice induced by soluble fms-like tyrosine kinase 1 (sFlt-1) showed accelerated glycolytic flux in the placenta labyrinth, together with the ATP shortage [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…There have been plenty of reports about mitochondrial destruction and dysfunction in the preeclamptic placentas [ 19 ]. The latest research has further claimed that preeclamptic trophoblasts are very likely to undergo the glycometabolic reprogramming to glycolysis [ 20 ]. Nonetheless, whether the overactive uteroplacental TLR4/NF- κ B signaling reprograms glycometabolism in the preeclamptic placentas remains to be settled.…”

Section: Introductionmentioning

confidence: 99%

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome‐Induced Pyroptosis via Inhibiting the TLR4/NF‐κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Zhang

Liu

Zhong

et al. 2021

Oxidative Medicine and Cellular Longevity

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NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

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“…AMPK is activated by an increase in the AMP to ATP ratio and hence, is reflective of a decline in energy status. In turn, AMPK activates metabolic enzymes that allow cells to switch on catabolic pathways that generate ATP, including glycolysis and fatty acid β-oxidation 41 . We did not observe differences in placental fatty acid oxidation between the lightest and heaviest of each fetal sex within the litter.…”

Section: Placental Signalling Pathwaysmentioning

confidence: 99%

Placental structure, function and mitochondrial phenotype relate to fetal size and sex in mice

Salazar‐Petres

Carvalho

López-Tello

et al. 2021

Preprint

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Fetal growth depends on placental function, which requires energy supplied by mitochondria. Here we investigated whether mitochondrial function in the placenta relates to growth of the lightest and heaviest fetuses of each sex within the litter of mice. Placentas from the lightest and heaviest fetuses were taken to evaluate placenta morphology (stereology), mitochondrial energetics (high-resolution respirometry), and mitochondrial regulators, nutrient transporters, hormone handling and signalling pathways (qPCR and western blotting). We found that mitochondrial complex I and II oxygen consumption rate was greater for placentas supporting the lightest female fetuses, although placental complex I abundance of the lightest females and complexes III and V of the lightest males were decreased compared to their heaviest counterparts. Expression of mitochondrial biogenesis (Nrf1) and fission (Drp1 and Fis1) genes was lower in the placenta from the lightest females, whilst biogenesis-related gene Tfam was greater in the placenta of the lightest male fetuses. Additionally, placental morphology and steroidogenic gene (Cyp17a1 and Cyp11a1) expression were aberrant for the lightest females, but glucose transporter (Glut1) expression lower in only the lightest males versus their heaviest counterparts. Differences in intra-litter placental phenotype were related to sex-dependent changes in the expression of hormone responsive (androgen receptor) and metabolic signalling pathways (AMPK, AKT, PPARγ). Thus, in normal mouse pregnancy, placental structure, function and mitochondrial phenotype are differentially responsive to growth of the female and the male fetus. This study may inform the design of sex-specific therapies for placental insufficiency and fetal growth abnormalities with life-long benefits for the offspring.

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Placental energy metabolism in health and disease—significance of development and implications for preeclampsia

Cited by 87 publications

References 132 publications

Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis

Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome‐Induced Pyroptosis via Inhibiting the TLR4/NF‐κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Placental structure, function and mitochondrial phenotype relate to fetal size and sex in mice

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