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Mechanisms Linking Metabolism and Reproductive Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 13026

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Special Issue Editors

Dr. Georgios Valsamakis

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2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, “Aretaieion” University Hospital, 11528 Athens, Greece
Interests: metabolism; obesity; appetite axis; endometrial environment
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Nikos F. Vlahos

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Guest Editor

2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
Interests: reproductive endocrinology; infertility; endometriosis; assisted reproduction; endoscopic surgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metabolic and reproductive disorders have a widespread incidence in our societies. Their effects affect a large part of the reproductive population. Their pathophysiology is not well understood. Important information is missing regarding their origins, etiology, and molecular mechanisms, thus preventing successful therapies. Metabolism and female reproduction are both regulated by centers located in the hypothalamus. There are data for the neuronal regulation of GnRH, which is located in hypothalamus. At the same time, inflammation of the nuclei which are centers of metabolism/appetite in the hypothalamus can cause obesity, and is associated with metabolic disorders. External stimuli such as diet and stress acting directly upon the hypothalamus can affect reproduction and metabolism. The surplus of nutrients and the reduced energy expenditure lead to alterations in metabolic pathways and to impairments in inter-relations between energy metabolism and reproduction. Reproductive health can be influenced by energetic states such as being under- and overweight, altering molecules and hormones. Obesity is associated with reproductive disorders, and there are conditions such as polycystic ovary syndrome which present with reproductive and metabolic disorders. Furthermore, during pregnancy, epigenetic changes can predispose the growing fetus to future metabolic and reproductive disorders. In this Special Issue, we aim to highlight molecular mechanisms that link metabolic and reproductive diseases, thus resulting in diseases which include both. Secondly, we hope to review the metabolic determinants of female reproduction. Thirdly, we aim to explore the effect of molecular metabolic parameters and their role in reproduction.

Dr. Georgios Valsamakis
Prof. Dr. Nikos F. Vlahos
Guest Editors

Manuscript Submission Information

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Keywords

metabolism
reproduction
hypothalamus
PCOS
endometrial environment
fertility
molecules

Published Papers (5 papers)

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Research

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17 pages, 3465 KiB

Open AccessArticle

Investigation of Metabolome Underlying the Biological Mechanisms of Acute Heat Stressed Granulosa Cells

by Abdul Sammad, Lirong Hu, Hanpeng Luo, Zaheer Abbas, Saqib Umer, Shanjiang Zhao, Qing Xu, Adnan Khan, Yajing Wang, Huabin Zhu and Yachun Wang

Int. J. Mol. Sci. 2022, 23(4), 2146; https://doi.org/10.3390/ijms23042146 - 15 Feb 2022

Cited by 12 | Viewed by 2529

Abstract

Heat stress affects granulosa cells and the ovarian follicular microenvironment, ultimately resulting in poor oocyte developmental competence. This study aims to investigate the metabo-lomics response of bovine granulosa cells (bGCs) to in vitro acute heat stress of 43 °C. Heat stress triggers oxidative stress-mediated apoptosis in cultured bGCs. Heat-stressed bGCs exhibited a time-dependent recovery of proliferation potential by 48 h. A total of 119 metabolites were identified through LC–MS/MS-based metabolomics of the spent culture media, out of which, 37 metabolites were determined as differentially involved in metabolic pathways related to bioenergetics support mechanisms and the physical adaptations of bGCs. Multiple analyses of metabolome data identified choline, citric acid, 3-hydroxy-3-methylglutaric acid, glutamine, and glycocyamine as being upregulated, while galactosamine, AICAR, ciliatine, 16-hydroxyhexadecanoic acid, lysine, succinic acid, uridine, xanthine, and uraconic acid were the important downregulated metabolites in acute heat stress. These differential metabolites were implicated in various important metabolic pathways directed towards bioenergetics support mechanisms including glycerophospholipid metabolism, the citrate cycle (TCA cycle), glyoxylate and dicarboxylate metabolism, and serine, threonine, and tyrosine metabolism. Our study presents important metabolites and metabolic pathways involved in the adaptation of bGCs to acute heat stress in vitro. Full article

(This article belongs to the Special Issue Mechanisms Linking Metabolism and Reproductive Diseases)

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19 pages, 4168 KiB

Open AccessArticle

SUCNR1 Is Expressed in Human Placenta and Mediates Angiogenesis: Significance in Gestational Diabetes

by Reham Atallah, Juergen Gindlhuber, Wolfgang Platzer, Thomas Bärnthaler, Eva Tatzl, Wolfgang Toller, Jasmin Strutz, Sonja Rittchen, Petra Luschnig, Ruth Birner-Gruenberger, Christian Wadsack and Akos Heinemann

Int. J. Mol. Sci. 2021, 22(21), 12048; https://doi.org/10.3390/ijms222112048 - 07 Nov 2021

Cited by 8 | Viewed by 3056

Abstract

Placental hypervascularization has been reported in pregnancy-related pathologies such as gestational diabetes mellitus (GDM). Nevertheless, the underlying causes behind this abnormality are not well understood. In this study, we addressed the expression of SUCNR1 (cognate succinate receptor) in human placental endothelial cells and hypothesized that the succinate–SUCNR1 axis might play a role in the placental hypervascularization reported in GDM. We measured significantly higher succinate levels in placental tissue lysates from women with GDM relative to matched controls. In parallel, SUCNR1 protein expression was upregulated in GDM tissue lysates as well as in isolated diabetic fetoplacental arterial endothelial cells (FpECAds). A positive correlation of SUCNR1 and vascular endothelial growth factor (VEGF) protein levels in tissue lysates indicated a potential link between the succinate–SUCNR1 axis and placental angiogenesis. In our in vitro experiments, succinate prompted hallmarks of angiogenesis in human umbilical vein endothelial cells (HUVECs) such as proliferation, migration and spheroid sprouting. These results were further validated in fetoplacental arterial endothelial cells (FpECAs), where succinate induced endothelial tube formation. VEGF gene expression was increased in response to succinate in both HUVECs and FpECAs. Yet, knockdown of SUCNR1 in HUVECs led to suppression of VEGF gene expression and abrogated the migratory ability and wound healing in response to succinate. In conclusion, our data underline SUCNR1 as a promising metabolic target in human placenta and as a potential driver of enhanced placental angiogenesis in GDM. Full article

(This article belongs to the Special Issue Mechanisms Linking Metabolism and Reproductive Diseases)

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13 pages, 3264 KiB

Open AccessArticle

Possible Roles of Calreticulin in Uterine Decidualization and Receptivity in Rats and Humans

by Mikihiro Yoshie, Kazuya Kusama, Risaka Tanaka, Takanori Okubo, Junya Kojima, Yotaro Takaesu, Keiichi Isaka, Hirotaka Nishi and Kazuhiro Tamura

Int. J. Mol. Sci. 2021, 22(19), 10505; https://doi.org/10.3390/ijms221910505 - 29 Sep 2021

Cited by 4 | Viewed by 2092

Abstract

Previous in vitro studies have suggested that calreticulin (CALR), which is responsible for the folding and quality control of glycoproteins, may be associated with decidualization. However, its precise role in regulating decidualization has not been explored in vivo. Here, we used pregnant rat models to examine endometrial CALR expression during the peri-implantation period. We also examined whether polypectomy, a procedure that could ameliorate infertility, alters the endometrial expression levels of CALR and several implantation factors in women diagnosed as infertile. In rats, uterine CALR was expressed at a high level at the implantation site, and a marked increase in CALR expression was observed in decidual cells of normal pregnancy. In addition, endometrial CALR expression was enhanced by either administration of estradiol-17β in the delayed implantation rat model or the artificial induction of decidualization in the pseudopregnant rat. In cultured stromal cells, siRNA-mediated silencing of CALR inhibited the decidual stimulus-induced expression of prolactin, decidual/trophoblast prolactin-related protein, and connexin 43. In humans, the endometrial expression levels of the mRNAs encoding CALR and the implantation-related factor insulin-like growth factor binding protein (IGFBP)-7 tended to increase after polypectomy. The strongest positive correlation between expression levels before polypectomy was observed for IGFBP-7 and CALR, and the strength of this correlation increased after the surgery. Thus, endometrial CALR may play a role in the formation of decidua, and the polypectomy of infertile patients may result in the co-operative expression of endometrial factors, including CALR, that could enhance endometrial receptivity. Full article

(This article belongs to the Special Issue Mechanisms Linking Metabolism and Reproductive Diseases)

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Review

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24 pages, 573 KiB

Open AccessReview

The Gestational Effects of Maternal Bone Marker Molecules on Fetal Growth, Metabolism and Long-Term Metabolic Health: A Systematic Review

by Angelos Dimas, Anastasia Politi, Alexandra Bargiota, Theodoros Panoskaltsis, Nikolaos F. Vlahos and Georgios Valsamakis

Int. J. Mol. Sci. 2022, 23(15), 8328; https://doi.org/10.3390/ijms23158328 - 28 Jul 2022

Cited by 4 | Viewed by 2053

Abstract

Fetal exposure in adverse environmental factors during intrauterine life can lead to various biological adjustments, affecting not only in utero development of the conceptus, but also its later metabolic and endocrine wellbeing. During human gestation, maternal bone turnover increases, as reflected by molecules involved in bone metabolism, such as vitamin D, osteocalcin, sclerostin, sRANKL, and osteoprotegerin; however, recent studies support their emerging role in endocrine functions and glucose homeostasis regulation. Herein, we sought to systematically review current knowledge on the effects of aforementioned maternal bone biomarkers during pregnancy on fetal intrauterine growth and metabolism, neonatal anthropometric measures at birth, as well as on future endocrine and metabolic wellbeing of the offspring. A growing body of literature converges on the view that maternal bone turnover is likely implicated in fetal growth, and at least to some extent, in neonatal and childhood body composition and metabolic wellbeing. Maternal sclerostin and sRANKL are positively linked with fetal abdominal circumference and subcutaneous fat deposition, contributing to greater birthweights. Vitamin D deficiency correlates with lower birthweights, while research is still needed on intrauterine fetal metabolism, as well as on vitamin D dosing supplementation during pregnancy, to diminish the risks of low birthweight or SGA neonates in high-risk populations. Full article

(This article belongs to the Special Issue Mechanisms Linking Metabolism and Reproductive Diseases)

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17 pages, 1388 KiB

Open AccessReview

The Gestational Effects of Maternal Appetite Axis Molecules on Fetal Growth, Metabolism and Long-Term Metabolic Health: A Systematic Review

by Angelos Dimas, Anastasia Politi, George Papaioannou, Thomas M. Barber, Martin O. Weickert, Dimitris K. Grammatopoulos, Sudhesh Kumar, Sophia Kalantaridou and Georgios Valsamakis

Int. J. Mol. Sci. 2022, 23(2), 695; https://doi.org/10.3390/ijms23020695 - 09 Jan 2022

Cited by 6 | Viewed by 2384

Abstract

Increased maternal food intake is considered a normal pregnancy adjustment. However, the overavailability of nutrients may lead to dysregulated fetal development and increased adiposity, with long-lasting effects on offspring in later life. Several gut-hormone molecules regulate maternal appetite, with both their orexigenic and anorectic effects being in a state of sensitive equilibrium. The aim of this manuscript is to systematically review literature on the effects of maternal gut-hormone molecules on fetal growth and metabolism, birth weight and the later metabolic health of offspring. Maternal serum ghrelin, leptin, IGF-1 and GLP-1 appear to influence fetal growth; however, a lack of consistent and strong correlations of maternal appetite axis hormones with birth weight and the concomitant correlation with fetal and birth waist circumference may suggest that these molecules primarily mediate fetal energy deposition mechanisms, preparing the fetus for survival after birth. Dysregulated intrauterine environments seem to have detrimental, sex-dependent effects on fetal energy stores, affecting not only fetal growth, fat mass deposition and birth weight, but also future metabolic and endocrine wellbeing of offspring. Full article

(This article belongs to the Special Issue Mechanisms Linking Metabolism and Reproductive Diseases)

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