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      Parturition dysfunction in obesity: time to target the pathobiology

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          Abstract

          Over a third of women of childbearing age in the United States are obese, and during pregnancy they are at increased risk for delayed labor onset and slow labor progress that often results in unplanned cesarean delivery. The biology behind this dysfunctional parturition is not well understood. Studies of obesity-induced changes in parturition physiology may facilitate approaches to optimize labor in obese women. In this review, we summarize known and proposed biologic effects of obesity on labor preparation, contraction/synchronization, and endurance, drawing on both clinical observation and experimental data. We present evidence from human and animal studies of interactions between obesity and parturition signaling in all elements of the birth process, including: delayed cervical ripening, prostaglandin insensitivity, amniotic membrane strengthening, decreased myometrial oxytocin receptor expression, decreased myocyte action potential initiation and contractility, decreased myocyte gap junction formation, and impaired myocyte neutralization of reactive oxygen species. We found convincing clinical data on the effect of obesity on labor initiation and successful delivery, but few studies on the underlying pathobiology. We suggest research opportunities and therapeutic interventions based on plausible biologic mechanisms.

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          The online version of this article (doi:10.1186/s12958-015-0129-6) contains supplementary material, which is available to authorized users.

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          Apelin, a newly identified adipokine up-regulated by insulin and obesity.

          The results presented herein demonstrate that apelin is expressed and secreted by both human and mouse adipocytes. Apelin mRNA levels in isolated adipocytes are close to other cell types present in white adipose tissue or other organs known to express apelin such as kidney, heart, and to a lesser extent brown adipose tissue. Apelin expression is increased during adipocyte differentiation stage. A comparison of four different models of obesity in mice showed a large increase in both apelin expression in fat cells and apelin plasma levels in all the hyperinsulinemia-associated obesities and clearly demonstrated that obesity or high-fat feeding are not the main determinants of the rise of apelin expression. The lack of insulin in streptozotocin-treated mice is associated with a decreased expression of apelin in adipocytes. Furthermore, apelin expression in fat cells is strongly inhibited by fasting and recovered after refeeding, in a similar way to insulin. A direct regulation of apelin expression by insulin is observed in both human and mouse adipocytes and clearly associated with the stimulation of phosphatidylinositol 3-kinase, protein kinase C, and MAPK. These data provide evidence that insulin exerts a direct control on apelin gene expression in adipocytes. In obese patients, both plasma apelin and insulin levels were significantly higher, suggesting that the regulation of apelin by insulin could influence blood concentrations of apelin. The present work identifies apelin as a novel adipocyte endocrine secretion and focuses on its potential link with obesity-associated variations of insulin sensitivity status.
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            Metabolic and body composition factors in subgroups of obesity: what do we know?

            Obesity is thought to be a heterogeneous disorder with several possible etiologies; therefore, by examining subtypes of obesity we attempt to understand obesity's heterogeneous nature. The purpose of this review was to investigate the roles of metabolic, body composition, and cardiovascular disease risk in subtypes of obesity. We briefly consider two subtypes of obesity that have been identified in the literature. One subset of individuals, termed the metabolically healthy, but obese (MHO), despite having large amounts of fat mass compared with at risk obese individuals shows a normal metabolic profile, but remarkably normal to high levels of insulin sensitivity. Preliminary evidence suggests that this could be due at least in part to lower visceral fat levels and earlier onset of obesity. A second subset, termed the metabolically obese, but normal weight (MONW), present with normal body mass index, but have significant risk factors for diabetes, metabolic syndrome, and cardiovascular disease, which could be due to higher fat mass and plasma triglycerides as well as higher visceral fat and liver content. We also briefly consider the potential role of adipose and gastrointestinal hormonal profiles in MHO and MONW individuals, which could lead to a better understanding of potential factors that may regulate their body composition. This information will eventually be invaluable in helping us understand factors that predispose to or protect obese individuals from metabolic and cardiovascular disease. Collectively, a greater understanding of the MHO and MONW individual has important implications for therapeutic decision making, the characterization of subjects in research protocols, and medical education.
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              Effect of Body Mass Index on pregnancy outcomes in nulliparous women delivering singleton babies

              Background The increasing prevalence of obesity in young women is a major public health concern. These trends have a major impact on pregnancy outcomes in these women, which have been documented by several researchers. In a population based cohort study, using routinely collected data, this paper examines the effect of increasing Body Mass Index (BMI) on pregnancy outcomes in nulliparous women delivering singleton babies. Methods This was a retrospective cohort study, based on all nulliparous women delivering singleton babies in Aberdeen between 1976 and 2005. Women were categorized into five groups – underweight (BMI 35 Kg/m2). Obstetric and perinatal outcomes were compared by univariate and multivariate analyses. Results In comparison with women of BMI 20 – 24.9, morbidly obese women faced the highest risk of pre-eclampsia {OR 7.2 (95% CI 4.7, 11.2)} and underweight women the lowest {OR 0.6 (95% CI 0.5, 0.7)}. Induced labour was highest in the morbidly obese {OR 1.8 (95% CI 1.3, 2.5)} and lowest in underweight women {OR 0.8 (95% CI 0.8, 0.9)}. Emergency Caesarean section rates were highest in the morbidly obese {OR 2.8 (95% CI 2.0, 3.9)}, and comparable in women with normal and low BMI. Obese women were more likely to have postpartum haemorrhage {OR 1.5 (95% CI 1.3, 1.7)} and preterm delivery ( 4,000 g was in the morbidly obese {OR 2.1 (95% CI 1.3, 3.2)} and the lowest in underweight women {OR 0.5 (95% CI 0.4, 0.6)}. Conclusion Increasing BMI is associated with increased incidence of pre-eclampsia, gestational hypertension, macrosomia, induction of labour and caesarean delivery; while underweight women had better pregnancy outcomes than women with normal BMI.
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                Author and article information

                Contributors
                Nicole.Carlson@emory.edu
                Teri.Hernandez@ucdenver.edu
                K.Joseph.Hurt@ucdenver.edu
                Journal
                Reprod Biol Endocrinol
                Reprod. Biol. Endocrinol
                Reproductive Biology and Endocrinology : RB&E
                BioMed Central (London )
                1477-7827
                18 December 2015
                18 December 2015
                2015
                : 13
                : 135
                Affiliations
                [ ]Emory University, Nell Hodgson Woodruff School of Nursing, 1520 Clifton Road NE, Atlanta, GA 30322 USA
                [ ]Department of Medicine, Division of Endocrinology, Metabolism, & Diabetes, College of Nursing, University of Colorado School of Medicine, 12801 E. 17th Ave, MS 8106, Aurora, CO 80045 USA
                [ ]Department of Obstetrics & Gynecology, Divisions of Maternal-Fetal Medicine & Reproductive Sciences, University of Colorado School of Medicine, 12700 East 19th Ave, MS 8613, Aurora, CO 80045 USA
                Author information
                http://orcid.org/0000-0001-6906-350X
                Article
                129
                10.1186/s12958-015-0129-6
                4683915
                26684329
                64cffbe7-bf2a-4db5-80f7-e21a610b7e45
                © Carlson et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 October 2015
                : 24 November 2015
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health (US);
                Award ID: #1F31NR014061-01A1
                Award Recipient :
                Funded by: March of Dimes
                Award ID: Graduate Nursing Grant
                Award Recipient :
                Funded by: University of Colorado
                Award ID: Touched by a Nurse Scholarship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: R01-DK101659
                Award Recipient :
                Funded by: March of Dimes
                Award ID: #5-FYI12-37
                Award Recipient :
                Funded by: NIH/NCATS
                Award ID: Colorado CTSA #UL1TR001082
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000071, National Institute of Child Health and Human Development;
                Award ID: #2K12HD001271
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2015

                Human biology
                cesarean section,cholesterol,dystocia,labor,leptin,meta-inflammation,myometrium,pregnancy,uterus
                Human biology
                cesarean section, cholesterol, dystocia, labor, leptin, meta-inflammation, myometrium, pregnancy, uterus

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